Publications by authors named "Anita Chugh"

25 Publications

  • Page 1 of 1

Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease.

J Biomol Struct Dyn 2020 May 5:1-16. Epub 2020 May 5.

Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the current COVID-19 pandemic. Worldwide this disease has infected over 2.5 million individuals with a mortality rate ranging from 5 to 10%. There are several efforts going on in the drug discovery to control the SARS-CoV-2 viral infection. The main protease (M) plays a critical role in viral replication and maturation, thus can serve as the primary drug target. To understand the structural evolution of M, we have performed phylogenetic and Sequence Similarity Network analysis, that depicted divergence of Coronaviridae M in five clusters specific to viral hosts. This clustering was corroborated with the comparison of M structures. Furthermore, it has been observed that backbone and binding site conformations are conserved despite variation in some of the residues. These attributes can be exploited to repurpose available viral protease inhibitors against SARS-CoV-2 M. In agreement with this, we performed screening of ∼7100 molecules including active ingredients present in the Ayurvedic anti-tussive medicines, anti-viral phytochemicals and synthetic anti-virals against SARS-CoV-2 M as the primary target. We identified several natural molecules like δ-viniferin, myricitrin, taiwanhomoflavone A, lactucopicrin 15-oxalate, nympholide A, afzelin, biorobin, hesperidin and phyllaemblicin B that strongly binds to SARS-CoV-2 M. Intrestingly, these molecules also showed strong binding with other potential targets of SARS-CoV-2 infection like viral receptor human angiotensin-converting enzyme 2 (hACE-2) and RNA dependent RNA polymerase (RdRp). We anticipate that our approach for identification of multi-target-directed ligand will provide new avenues for drug discovery against SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1760137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212545PMC
May 2020

Discovery of Potent and Selective A Antagonists with Efficacy in Animal Models of Parkinson's Disease and Depression.

ACS Med Chem Lett 2017 Aug 5;8(8):835-840. Epub 2017 Jul 5.

Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.

Adenosine A receptor (AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-]purin-2-one derivatives that displays functional antagonism of the A receptor with a high degree of selectivity over A, A, and A receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound . Compound endowed with satisfactory and pharmacokinetics properties. Compound demonstrated robust oral efficacies in two commonly used models of Parkinson's disease (haloperidol-induced catalepsy and 6-OHDA lesioned rat models) and depression (TST and FST mice models).
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http://dx.doi.org/10.1021/acsmedchemlett.7b00175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554908PMC
August 2017

Design and synthesis of novel xanthine derivatives as potent and selective A adenosine receptor antagonists for the treatment of chronic inflammatory airway diseases.

Eur J Med Chem 2017 Jul 12;134:218-229. Epub 2017 Apr 12.

Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India. Electronic address:

Adenosine induces bronchial hyperresponsiveness and inflammation in asthmatics through activation of A adenosine receptor (AAdoR). Selective antagonists have been shown to attenuate airway reactivity and improve inflammatory conditions in pre-clinical studies. Hence, the identification of novel, potent and selective AAdoR antagonist may be beneficial for the potential treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). Towards this effort, we explored several prop-2-ynylated C8-aryl or heteroaryl substitutions on xanthine chemotype and found that 1-prop-2-ynyl-1H-pyrazol-4-yl moiety was better tolerated at the C8 position. Compound 59, exhibited binding affinity (K) of 62 nM but was non-selective for AAdoR over other AdoRs. Incorporation of substituted phenyl on the terminal acetylene increased the binding affinity (K) significantly to <10 nM. Various substitutions on terminal phenyl group and different alkyl substitutions on N-1 and N-3 were explored to improve the potency, selectivity for AAdoR and the solubility. In general, compounds with meta-substituted phenyl provided better selectivity for AAdoR compared to that of para-substituted analogs. Substitutions such as basic amines like pyrrolidine, piperidine, piperazine or cycloalkyls with polar group were tried on terminal acetylene, keeping in mind the poor solubility of xanthine analogs in general. However, these substitutions led to a decrease in affinity compared to compound 59. Subsequent SAR optimization resulted in identification of compound 46 with high human AAdoR affinity (K = 13 nM), selectivity against other AdoR subtypes and with good pharmacokinetic properties. It was found to be a potent functional AAdoR antagonist with a K of 8 nM in cAMP assay in hA-HEK293 cells and an IC of 107 nM in IL6 assay in NIH-3T3 cells. Docking study was performed to rationalize the observed affinity data. Structure-activity relationship (SAR) studies also led to identification of compound 36 as a potent AAdoR antagonist with K of 1.8 nM in cAMP assay and good aqueous solubility of 529 μM at neutral pH. Compound 46 was further tested for in vivo efficacy and found to be efficacious in ovalbumin-induced allergic asthma model in mice.
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http://dx.doi.org/10.1016/j.ejmech.2017.04.014DOI Listing
July 2017

Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia.

Eur J Med Chem 2017 Jun 24;133:268-286. Epub 2017 Mar 24.

Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.

Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia.
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http://dx.doi.org/10.1016/j.ejmech.2017.03.042DOI Listing
June 2017

Design and synthesis of novel, potent and selective hypoxanthine analogs as adenosine A receptor antagonists and their biological evaluation.

Bioorg Med Chem 2017 03 16;25(6):1963-1975. Epub 2017 Feb 16.

Drug Discovery Unit, Advinus Therapeutics Ltd., Hinjewadi, Pune 411 057, India.

Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in vivo primary acute diuresis model. The compound demonstrated significant diuretic activity in this model.
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http://dx.doi.org/10.1016/j.bmc.2017.02.029DOI Listing
March 2017

A adenosine receptor antagonists: Design, synthesis and biological evaluation of novel xanthine derivatives.

Eur J Med Chem 2017 Feb 8;127:986-996. Epub 2016 Nov 8.

Department of Discovery Chemistry, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of Discovery Biology, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India; Department of DMPK, Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune, 411 057, India. Electronic address:

AdoR is a low affinity adenosine receptor that functions by Gs mediated elevation of cAMP and subsequent downstream signaling. The receptor has been implicated in lung inflammatory disorders like COPD and asthma. Several potent and selective AAdoR antagonists have been reported in literature, however most of the compounds suffer from poor pharmacokinetic profile. Therefore, with the aim to identify novel, potent and selective AAdoR antagonists with improved pharmacokinetic properties, we first explored more constrained form of MRS-1754 (4). To improve the metabolic stability, several linker modifications were attempted as replacement of amide linker along with different phenyl or other heteroaryls between C8 position of xanthine head group and terminal phenyl ring. SAR optimization resulted in identification of two novel AAdoR antagonists, 8-{1-[5-Oxo-1-(4-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-xanthine (31) and 8-(1-{2-Oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-1H-pyrazol-4-yl)-1,3-dipropyl-xanthine (65), with high binding affinity (K = 1 and 1.5 nM, respectively) and selectivity for AAdoR with very good functional potency of 0.9 nM and 4 nM, respectively. Compound 31 and 65 also displayed good pharmacokinetic properties in mice with 27% and 65% oral bioavailability respectively. When evaluated in in vivo mice model of asthma, compound 65 also inhibited airway inflammation and airway reactivity in ovalbumin induced allergic asthma at 3 mpk dose.
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http://dx.doi.org/10.1016/j.ejmech.2016.11.007DOI Listing
February 2017

Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain L-2-hydroxy acid oxidase.

Bioorg Med Chem Lett 2012 Jul 11;22(13):4341-7. Epub 2012 May 11.

Drug Discovery Facility, Advinus Therapeutics, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.

Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.
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http://dx.doi.org/10.1016/j.bmcl.2012.05.020DOI Listing
July 2012

Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats.

ACS Med Chem Lett 2011 Dec 7;2(12):919-23. Epub 2011 Oct 7.

Merck Research Laboratories , Rahway, New Jersey 07065, United States.

l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetate-treated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension.
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http://dx.doi.org/10.1021/ml2001938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018152PMC
December 2011

Discovery of a potent and selective small molecule hGPR91 antagonist.

Bioorg Med Chem Lett 2011 Jun 28;21(12):3596-602. Epub 2011 Apr 28.

Drug Discovery Facility, Advinus Therapeutics, Quantum Towers, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune, India.

GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 μM)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5 g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; >100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; >100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay.
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http://dx.doi.org/10.1016/j.bmcl.2011.04.091DOI Listing
June 2011

RBx-0597, a potent, selective and slow-binding inhibitor of dipeptidyl peptidase-IV for the treatment of type 2 diabetes.

Eur J Pharmacol 2011 Feb 9;652(1-3):157-63. Epub 2010 Jun 9.

Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana-122001, India.

Dipeptidyl peptidase IV (DPP-IV) inhibiton is a well recognized approach to treat Type 2 diabetes. RBx-0597 is a novel DPP-IV inhibitor discovered in our laboratory. The aim of the present study was to characterize the pharmacological profiles of RBx-0597 in vitro and in vivo as an anti-diabetic agent. RBx-0597 inhibited human, mouse and rat plasma DPP-IV activity with IC(50) values of 32, 31 and 39nM respectively. RBx-0597 exhibited significant selectivity over dipeptidyl peptidase8 (DPP-8), dipeptidyl peptidase9 (DPP-9) (150-300 fold) and other proline-specific proteases (>200-2000 fold). Kinetic analysis revealed that RBx-0597 is a competitive and slow binding DPP-IV inhibitor. In ob/ob mice, RBx-0597 (10mg/kg) inhibited plasma DPP-IV activity upto 50% 8h post-dose and showed a dose-dependent glucose excursion. RBx-0597 (10mg/kg) showed a significant glucose lowering effect (∼25% AUC of △ blood glucose) which was sustained till 12h, significantly increased the active glucagon-like peptide-1(GLP-1) and insulin levels. It showed a favourable pharmacokinetic profile (plasma clearance:174ml/min/kg; C(max) 292ng/ml; T(1/2) 0.28h; T(max) 0.75h and V(ss) 4.13L/kg) in Wistar rats with the oral bioavailability (F(oral)) of 65%. In summary, the present studies indicate that RBx-0597 is a novel DPP-IV inhibitor with anti-hyperglycemic effect and a promising candidate for further development as a drug for the treatment of type 2 diabetes.
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http://dx.doi.org/10.1016/j.ejphar.2010.06.001DOI Listing
February 2011

Ratiometric Ca+2 measurement in human recombinant muscarinic receptor subtypes using the Flexstation scanning fluorometer.

J Recept Signal Transduct Res 2009 ;29(2):100-6

Department of Pharmacology, Ranbaxy Research Laboratories, Udyog Vihar, India.

In modern drug discovery, numerous assay formats are available to screen and quantitate receptor-ligand interactions. Radioactive assays are "gold standard" because they are fast, easy, and reproducible; however, they are hazardous, produce radioactive waste, require special lab conditions, and are expensive on a large scale. Thus, it provides a lot of importance to the "mix & measure" assays that have an optical readout. Fluorescence techniques are likely to be among the most important detection approaches used for high throughput screening due to their high sensitivity and amenability to automation. The aim of the present study was to determine the functional antagonistic affinities of standard muscarinic antagonists in CHO cells over expressing m1, m3, and m5 receptors and to compare them with the respective binding affinities. This study was further extended to elucidate that Ca+2 measurement assays can serve as a functional screening tool for GPCRs. For this purpose, standard muscarinic receptor antagonists, namely, tolterodine, oxybutynin, and atropine were used. We determined and compared the IC50 values of these three standard inhibitors in fura 2 AM loaded m1, m3, and m5 overexpressing CHO cells and in radioligand binding assay. Both the assays exhibited comparable rank order potencies of the standard inhibitors. This study suggests that Ca+2 mobilization assays can be an alternate to radioligand binding assays.
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http://dx.doi.org/10.1080/10799890902802634DOI Listing
August 2009

RBx 6198: a novel alpha1-adrenoceptor antagonist for the treatment of benign prostatic hyperplasia.

Eur J Pharmacol 2009 Apr 23;607(1-3):213-9. Epub 2009 Feb 23.

Department of Pharmacology, Ranbaxy Research Laboratories, Plot -20, Sector-18, Gurgaon, 122015, India.

The present study, investigates the effect of RBx 6198, 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-propyl}-3a, 4, 7, 7a-tetrahydro-isoindole-1, 3,-dione, a novel alpha(1)-adrenoceptor antagonist, in both in vitro and in vivo test systems. RBx 6198 is a potent (nanomolar affinity) alpha(1A)-adrenoceptor antagonist with demonstrable uroselectivity in anaesthesized dog model. In radioligand binding studies using human recombinant receptors, RBx 6198 exhibited high selectivity (approximately 50 fold) for the alpha(1A)-adrenoceptor subtype as compared to alpha(1B)-adrenoceptor subtype. In order to assess tissue selectivity, the antagonistic effect of RBx 6198 on the phenylephrine induced contractile response of isolated rat prostate, spleen and aorta was characterized. RBx 6198 was 8 fold more potent in inhibiting phenylephrine-evoked contractions of isolated tissues compared to tamsulosin. However, the compound was non-selective for alpha(1A) vs. alpha(1D)-adrenoceptor like tamsulosin. In anaesthetized beagle dogs RBx 6198 suppressed the intraurethral pressure response to phenylephrine to a greater extent than the mean arterial pressure response thereby demonstrating uroselectivity consistent with in vitro binding and functional data. RBx 6198 was 6.4 fold more uroselective as compared to tamsulosin after i.v. route dose administration. Taken together all results from preclinical studies, it is suggested that RBx 6198 is a novel alpha(1)-adrenoceptor antagonist that exhibited improved pharmacological profile over tamsulosin in both in vitro and in vivo.
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http://dx.doi.org/10.1016/j.ejphar.2009.02.026DOI Listing
April 2009

Discovery of conformationally rigid 3-azabicyclo[3.1.0]hexane-derived dipeptidyl peptidase-IV inhibitors.

Bioorg Med Chem Lett 2008 Jul 2;18(14):4087-91. Epub 2008 Jul 2.

Department of Medicinal Chemistry, Ranbaxy Research Laboratories, Gurgaon 122001, India.

The induction of conformationally restricted N-(aryl or heteroaryl)-3-azabicyclo[3.1.0]hexane derivatives at P(2) region of compounds of 2-cyanopyrrolidine class was explored to develop novel DPP-IV inhibitors. The synthesis, structure-activity relationship, and selectivity against related proteases are delineated.
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http://dx.doi.org/10.1016/j.bmcl.2008.05.101DOI Listing
July 2008

Synthesis and optimization of novel and selective muscarinic M(3) receptor antagonists.

Bioorg Med Chem Lett 2007 Sep 30;17(18):5256-60. Epub 2007 Jun 30.

Ranbaxy Research Laboratories, New Drug Discovery Research, Department of Medicinal Chemistry, Gurgaon, Haryana 122 001, India.

A series of constrained piperidine analogues were synthesized as novel muscarinic M(3) receptor antagonists. Evaluation of these compounds in binding assays revealed that they not only have high affinity for the M(3) receptor but also have high selectivity over the M(2) receptor.
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http://dx.doi.org/10.1016/j.bmcl.2007.06.081DOI Listing
September 2007

Comparative in vivo uroselectivity profiles of anticholinergics, tested in a novel anesthetized rabbit model.

Eur J Pharmacol 2007 Oct 13;572(2-3):207-12. Epub 2007 Jun 13.

Department of Pharmacology, Ranbaxy Research Laboratories, Plot-20, Sector-18, Gurgaon 122 015, India.

The aim of this study was to describe a new experimental animal model for simultaneous measurement of carbachol-induced increase in intravesical pressure and salivary secretion in rabbits. Further, we also compared the in vivo potency and urinary bladder versus salivary gland selectivity profiles of Oxybutynin, Tolterodine, Solifenacin and Darifenacin. The intravesical pressure and salivary secretion were evoked by intra-arterial injection of carbachol (1.5 microg/kg). The carbachol-induced increase in intravesical pressure and salivation was simultaneously recorded before and after increasing doses of test drugs administered intravenously. The basal mean changes in intravesical pressure and salivation subsequent to carbachol administration were in the range of 6.7-7.5 mm Hg and 0.5-0.7 g respectively. Repeated administration of vehicle did not elicit any appreciable changes in intravesical pressure and salivary secretion to carbachol administration from the basal values till 3 h. All the test drugs exhibited a dose-dependent inhibition of carbachol-induced increase in intravesical pressure and salivary secretion. Darifenacin demonstrated a greater potency compared to other muscarinic receptor antagonists for inhibiting carbachol-induced increase in intravesical pressure. It also exhibited functional selectivity for the urinary bladder versus salivary gland. In contrast, Oxybutynin was functionally more selective in inhibiting carbachol-induced increase in salivary secretion. The observed urinary bladder versus salivary selectivity values were 0.6+/-0.2, 1.1+/-0.2, 1.7+/-0.5, and 2.3+/-0.5 for Oxybutynin, Tolterodine, Solifenacin and Darifenacin respectively. These results suggest that the functional selectivity of muscarinic receptor antagonists between urinary bladder and salivary glands can be readily detected in this model. Thus rabbits may represent a useful animal model for evaluating putative bladder selective muscarinic receptor antagonists for the treatment of overactive bladder.
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http://dx.doi.org/10.1016/j.ejphar.2007.06.009DOI Listing
October 2007

Role of peripheral 5-HT1A receptors in detrusor over activity associated with partial bladder outlet obstruction in female rats.

Eur J Pharmacol 2007 Apr 1;561(1-3):189-93. Epub 2007 Feb 1.

Department of Pharmacology, NDDR, Ranbaxy Research Laboratories, Plot No 20, Udyog Vihar Industrial Area, Sector 18, Gurgaon-122001, Haryana, India.

We have investigated the role of peripheral 5-hydroxytryptamine 1A (5-HT(1A)) receptors and their probable up-regulation in rat model of partial bladder outlet obstruction. Bladder outlet obstruction was induced in adult female rats, hypertropic bladders were harvested after 6 weeks and isometric contractions of bladder strips were recorded. A marked spontaneous activity of the bladder was observed in obstructed bladder strips compared to control strips. The effect of alpha(1A/1D)-adrenergic antagonist, tamsulosin, was observed to be inhibitory on the spontaneous contractions albeit at higher doses (10, 30 and 100 nM). As tamsulosin at higher doses also has high affinity for 5-HT(1A) receptors, the role of peripheral 5-HT(1A) receptors in overactive bladder was hypothesized. 8-hydroxy-2-(di-n-propylamino) tetralin [8-OH-DPAT], a selective 5-HT(1A) receptor agonist, dose-dependently induced significant contractions in the obstructed bladder strips, compared to control bladders. N-[2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl]-N-pyridin-2-yl-cyclohexanecarboxamide dihydrochloride (WAY-100635), a selective 5-HT(1A) receptor antagonist, competitively antagonized the contractile response to 8-OH-DPAT in obstructed bladder strips in a dose-dependent manner. Tamsulosin at a higher dose was also observed to antagonize the responses to 8-OH-DPAT. Taken together, these observations suggest the involvement of peripheral 5-HT(1A) receptors in detrusor over activity associated with bladder outlet obstruction in female rats.
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http://dx.doi.org/10.1016/j.ejphar.2007.01.031DOI Listing
April 2007

Molecular cloning, stable expression and cellular localization of human alpha1-adrenergic receptor subtypes: effect of charcoal/dextran treated serum on expression and localization of alpha1D -adrenergic receptor.

Biotechnol Lett 2006 Nov 16;28(21):1731-9. Epub 2006 Aug 16.

Department of Biotechnology, Ranbaxy Research Laboratories, Plot No. 20, Sector 18, Udyog Vihar Industrial Area, Gurgaon, 122001 Haryana, India.

The cDNAs encoding for three subtypes of adrenergic receptors, alpha1A-, alpha1B- and alpha1D-ARs, were cloned and expressed in HEK 293 cells. Expression of alpha1A- and alpha1B-AR subtypes in HEK 293 cells was stable even with increased passages but that of alpha1D-AR was not. Cellular localization studies using immunofluorescence and flow cytometry revealed that expression of alpha1A- and alpha1B-ARs was primarily localized on the cell membrane whereas expression of alpha1D-AR was predominantly intracellular. Our studies clearly demonstrated that the culturing of the recombinant cell lines expressing alpha1D-AR in charcoal/dextran treated fetal bovine serum (FBS) resulted in targeting of alpha1D-AR to the cell membrane and thus, significantly improving its stability and availability for ligand binding studies.
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http://dx.doi.org/10.1007/s10529-006-9148-xDOI Listing
November 2006

Statins and myotoxicity: a therapeutic limitation.

Expert Opin Drug Saf 2006 Sep;5(5):651-66

Ranbaxy Research Laboratories, Metabolic & Urology Group, New Drug Discovery Research, Gurgaon-122001, Haryana, India.

Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors represent the most successful class of drugs for the treatment of hypercholesterolaemia and dyslipidaemia implicated in the pathogenesis of coronary heart disease and atherosclerosis. However, the popular profile of statins in terms of efficacy has been maligned by its adverse events. The myotoxicity, ranging from mild myopathy to serious rhabdomyolysis, associated with HMG-CoA reductase inhibitors, during treatment of hypercholesterolaemia is of paramount importance. Rhabdomyolysis is a rare but idiosyncratic muscle wasting disorder of different etiologies. Statin-associated rhabdomyolysis causes skeletal muscle injury by self-perpetuating events leading to fatal irreversible renal damage through a series of biochemical reactions. Preferential distribution and action of statins in liver could be the key to minimise myotoxicity concerns. Hepato-specific distribution of statins is governed by various factors such as physicochemical properties, pharmacokinetic properties and selective transporter-mediated uptake in liver rather in extrahepatic cells. The interactions of statins with concomitant drugs of different classes merit attention for their safety profile. Although pharmacokinetic as well as pharmacodynamic interactions have been implicated in pathophysiology of statin-induced muscle wasting, the underlying mechanism is not clearly understood. Besides, pharmacokinetic and phramcodynamic factors, statin-associated myotoxcity may also implicate pharmacogenomic factors. The pharmacogenomics characterised by CYP polymorphism and other genetic factors is responsible for inter-individual variations to efficacy and tolerability of statins. The pathophysiological mechanisms may include statin-induced differences in cholesterol:phospholipid ratio, isoprenoid levels, small GTP binding proteins and apoptosis. However, the present understanding of pathophysiological mechanisms, does not offer a reliable approach to address the same at preclinical level. Although statin-associated myotoxicity affects compliance, quality of life of patient and discontinuation rate, yet the low incidence of myotoxicty including rhabdomyolysis and less severity of commonly occurring myopathy and myalgia do not raise doubts about the clinical efficacy and tolerability of statins. Medical management of myotoxicity seems to be pivotal for the proper compliance of patients with statin treatment. The appropriate and judicious use of drugs would substantially reduce the likelihood of developing clinically important myopathy.
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http://dx.doi.org/10.1517/14740338.5.5.651DOI Listing
September 2006

Intermittent claudication: an overview.

Atherosclerosis 2006 Aug 28;187(2):221-37. Epub 2005 Dec 28.

New Drug Discovery Research, Department of Pharmacology, Ranbaxy Laboratories Limited, R&D, Plot 20, Sector 18, Udyog Vihar Industrial Area, Gurgaon 122001, Haryana, India.

Intermittent claudication (IC) is defined by leg muscle pain, cramping and fatigue brought on by ambulation/exercise; relieved on rest; and caused by inadequate blood supply and is the primary symptom of peripheral arterial disease (PAD). PAD has a detrimental effect on the quality of life. PAD is a debilitating atherosclerotic disease of the lower limbs and is associated with an increased risk of cardiovascular morbidity and mortality. IC is an extremely important marker of atheroma. Up to 60% patients with IC have significant underlying coronary and/or carotid disease and 40% of all patients suffering from IC die or suffer a stroke within 5 years of presentation. The therapeutic intervention of IC essentially aims at providing symptomatic relief and reducing the systemic cardiovascular complications. Although exercise therapy is one of the most efficacious conservative treatments for claudication, the pharmacotherapeutic goals can be best achieved through an increase in the walking capacity to improve quality of life and a decrease in rates of amputation. In the development of treatment for IC, an aggressive non-pharmacological intervention and pharmacological treatment of the risk factors associated with IC are considered. In the next 2 years, the results of major trials of drugs that stabilize and regress atherosclerosis such as statins and angiotensin converting enzyme inhibitors, and anti-platelet agents, recombinant growth factors and immune modulators will be available for IC. Levocarnitine (l-carnitine) and a derivative, propionyl levocarnitine, are emerging agents that increase the pain-free walking and improve the quality of life in IC patients by working at the metabolism and exercise performance of ischemic muscles. This article provides a comprehensive review of the pathophysiology involved, diagnosis of IC and existing and emerging pharmacotherapies with rationale for their use in its treatment.
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http://dx.doi.org/10.1016/j.atherosclerosis.2005.11.027DOI Listing
August 2006

High level stable expression of pharmacologically active human M1-M5 muscarinic receptor subtypes in mammalian cells.

Biotechnol Lett 2006 Jan;28(2):121-9

Department of Biotechnology, Ranbaxy Research Laboratories, Udyog Vihar Industrial Area, Gurgaon, Haryana, India.

cDNAs encoding for five mAChR subtypes (M1-M5) were cloned under different promoters in various eukaryotic vectors and each subtype was expressed in different mammalian cell lines. CHO-K1 cell line was the best for generating stable cell lines expressing muscarinic receptors. Immunofluorescence and flow cytometry revealed that expression of M1-M5 was primarily localized on the cell membrane. Western blotting and radio-ligand binding studies revealed that expression of each receptor was stable at higher passages.
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http://dx.doi.org/10.1007/s10529-005-5130-2DOI Listing
January 2006

WITHDRAWN: Derivatives of cis-1,2,3,6-tetrahydrophthalimide for the treatment of benign prostatic hyperplasia.

Bioorg Med Chem Lett 2005 Nov 3. Epub 2005 Nov 3.

Department of Medicinal Chemistry, New Drug Discovery Research, Ranbaxy Research Laboratories, Plot 20, Sector 18, Gurgaon 122001, India. Electronic address:

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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http://dx.doi.org/10.1016/j.bmcl.2005.10.043DOI Listing
November 2005

Benign prostatic hyperplasia: an insight into current investigational medical therapies.

Expert Opin Investig Drugs 2005 Nov;14(11):1359-72

Urology and Metabolic Group, NDDR, Ranbaxy Research Laboratories, Gurgaon-122001, Haryana, India.

Benign prostatic hyperplasia (BPH) is a leading disorder of the elderly male population that is characterised by a progressive enlargement of prostatic tissue, resulting in obstruction of the proximal urethra and causing urinary flow disturbances. The pathophysiology of BPH associated with lower urinary tract symptoms is characterised by increased adrenergic tone (dynamic component) leading to smooth muscle contraction and prostatic overgrowth due to androgenic stimulation (static component); therefore, the therapeutic armamentarium of BPH can be broadly divided into antiadrenergic and antiandrogenic approaches. alpha1-Adrenoceptor antagonists and 5alpha-reductase inhibitors are well-established representatives of the two categories, respectively. Other antiandrogenic approaches involve gonadotropin-releasing hormone agonists and antagonists for the treatment of prostate hyperplasia. Apart from these approaches, new approaches with novel targets are emerging. The advent of new therapies is, however, more oriented towards the static component. These involve metabolic factors (hexokinase inhibitor), growth factors (vitamin D3 analogues), oxytocin antagonists and gonadotropin-releasing hormone Gi agonist-based therapies. Gene therapy and photodynamic therapies are other emerging therapies for relieving symptoms in BPH patients. With the initial success of upcoming targets, the unmet need to develop an efficacious and relatively safe therapeutic modality is discussed. Nevertheless, their long-term safety and efficacy needs to be evaluated in large-scale clinical trials. The future also belongs to combination therapies to combat both dynamic and static disease components and for extended indications such as micturition disorder and non-bacterial prostatitis.
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http://dx.doi.org/10.1517/13543784.14.11.1359DOI Listing
November 2005

Design, synthesis and activity of novel derivatives of oxybutynin and tolterodine.

Bioorg Med Chem Lett 2005 Apr;15(8):2093-6

Ranbaxy Research Laboratories, New Drug Discovery Research, Department of Medicinal Chemistry, Gurgaon 122 001, Haryana, India.

Novel derivatives of Tolterodine (1) and Oxybutynin (2) have been designed using conformationally restricted azabicyclics as replacement for open-chain amines. The synthesis and structure-activity relationships are presented.
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http://dx.doi.org/10.1016/j.bmcl.2005.02.036DOI Listing
April 2005

Squalene epoxidase as hypocholesterolemic drug target revisited.

Prog Lipid Res 2003 Jan;42(1):37-50

New Drug Discovery Research, Department of Pharmacology, Ranbaxy Laboratories Ltd., Plot 20, Sector-18, Udyog Vihar Industrial Area, Gurgaon-122 001, Haryana, India.

Therapeutic success of statins has distinctly established inhibition of de novo hepatic cholesterol synthesis as an effective approach to lower plasma LDL-cholesterol, the major risk factor for atherosclerosis and coronary heart disease. Statins inhibit HMG CoA reductase, a rate limiting enzyme which catalyses conversion of HMG CoA to mevalonic acid. However, in this process statins also inhibit the synthesis of several non-sterols e.g. dolichols and ubiquinone, which are implicated in side effects observed with statins. This prompted many major pharmaceutical companies in 1990s to target selective cholesterol synthesis beyond farnesyl pyrophosphate. The enzymes squalene synthetase, squalene epoxidase and oxidosqualene cyclase were identified as potential targets. Though inhibitors of these enzymes have been developed, till date no compound has been reported to have entered clinical trials. We evaluated the literature to understand merits and demerits of pursuing squalene epoxidase as a target for hypocholesterolemic drug development. Squalene epoxidase catalyses the conversion of squalene to 2,3-oxidosqualene. Although it has been extensively exploited for antifungal drug development, it has received little attention as a target for hypocholesterolemic drug design. This enzyme though recognized in the early 1970s was cloned 25 years later. This enzyme is an attractive step for pharmacotherapeutic intervention as it is the secondary rate limiting enzyme and blocking cholesterol synthesis at this step may result in accumulation of only squalene which is known to be stable and non toxic. Synthesis of several potent, orally bioavailable inhibitors of squalene epoxidase has been reported from Yamonuchi, Pierre Fabre and Banyu pharmaceuticals. Preclinical studies with these inhibitors have clearly demonstrated the potential of squalene epoxidase inhibitors as hypocholesterolemic agents. Hypochloesterolemic therapy is intended for prolonged duration and safety is an important determinant in clinical success. Lack of clinical trials, despite demonstrated preclinical efficacy by oral route, prompted us to evaluate safety concerns with squalene epoxidase inhibitors. In dogs, NB-598, a potent competitive squalene epoxidase inhibitor has been reported to exhibit signs of dermatitis like toxicity which has been attributed by some reviewers to accumulation of squalene in skin cells. Tellurium, a non-competitive inhibitor of squalene epoxidase has been associated with neuropathy in weanling rats. On the other hand, increased plasma levels of squalene in animals and humans (such as occurring subsequent to dietary olive oil or squalene administration) are safe and associated with beneficial effect such as chemoprevention and hypocholesterolemic activity. In our view, high circulating levels of squalene epoxidase inhibitor may be responsible for dermatitis and neuropathy. Competitive inhibition and pharmacokinetic profile minimizing circulating plasma levels (e.g. by hepatic sequestration and high first pass metabolism) could be important determinants in circumventing safety concerns of squalene epoxidase inhibitors. Recently, cholesterol-lowering effect of green tea has been attributed to potent squalene epoxidase inhibition, which can be consumed in much higher doses without toxicological effect. These facts strengthen optimism for developing clinically safe squalene epoxidase inhibitors. Put in perspective squalene epoxidase appears to be undervalued target which merits attention for development of better hypocholesterolemic drugs.
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http://dx.doi.org/10.1016/s0163-7827(02)00029-2DOI Listing
January 2003

Opposing effect of apomorphine on antinociceptive activity of morphine: a dose-dependent phenomenon.

Pain 1989 Feb;36(2):263-269

Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029 India.

Apomorphine, when administered intracerebroventricularly (0.05 mg/kg) to rats, increased tail-flick latency (a spinal nociceptive response). However, intraperitoneal administration at doses of 1, 3 and 10 mg/kg had no effect, probably because of a tonic supraspinal inhibitory influence on spinal dopaminergic neurones involved in segmental nociceptive processes. Depending on the doses administered, intraperitoneal administration of apomorphine exhibited opposite effects on antinociceptive activity of morphine. Pretreatment with a low dose of apomorphine (1 mg/kg) attenuated, whereas, a high dose (10 mg/kg) potentiated morphine-induced antinociception. Dopamine antagonists, in doses that preferentially block autoreceptors, i.e., haloperidol (0.1 mg/kg, i.p.) and (-)-sulpiride (5 mg/kg, i.p.), antagonised the attenuation of morphine antinociception by a low dose of apomorphine, while treatment with a high dose of haloperidol (1 mg/kg, i.p.) and pimozide (1.25 mg/kg, i.p.) completely antagonised the potentiating effect of a high dose of apomorphine on the antinociceptive activity of morphine. The attenuation of morphine antinociception thus appears to be due to decreased dopaminergic activity as a result of preferential dopamine autoreceptor stimulation by a low dose of apomorphine, whereas potentiation with a high dose of apomorphine is caused by enhanced dopaminergic activity via postsynaptic receptor stimulation.
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http://dx.doi.org/10.1016/0304-3959(89)90032-8DOI Listing
February 1989