Publications by authors named "Mark J Macielag"

30 Publications

  • Page 1 of 1

Discovery of a Novel Series of Pyridone-Based EP3 Antagonists for the Treatment of Type 2 Diabetes.

ACS Med Chem Lett 2021 Mar 26;12(3):451-458. Epub 2021 Feb 26.

Discovery Chemistry, Cardiovascular and Metabolic Research, Janssen Research & Development, LLC, 1400 McKean Roads, Box 776, Spring House, Pennsylvania 19477, United States.

A novel series of pyridones were discovered as potent EP3 antagonists. Optimization guided by EP3 binding and functional assays as well as by eADME and PK profiling led to multiple compounds with good physical properties, excellent oral bioavailability, and a clean in vitro safety profile. Compound was identified as a lead compound as evidenced by the reversal of sulprostone-induced suppression of glucose-stimulated insulin secretion in INS 1E β-cells in vitro and in a rat ivGTT model in vivo. A glutathione adduction liability was eliminated by replacing the naphthalene of structure with the indazole ring of structure .
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http://dx.doi.org/10.1021/acsmedchemlett.0c00667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957929PMC
March 2021

GPR120 agonists for the treatment of diabetes: a patent review (2014 present).

Expert Opin Ther Pat 2020 Oct 30;30(10):729-742. Epub 2020 Aug 30.

Discovery Chemistry, Janssen Research and Development , Spring House, PA, USA.

Introduction: G protein-coupled receptor 120 (GPR120) is a G coupled GPCR specifically activated by long-chain fatty acids (LCFAs). Functionally, it has been identified as a member of a family of lipid-binding free fatty acid receptors including GPR40, GPR41, and GPR43. Upon stimulation by LCFAs, GPR120 can directly or indirectly modulate hormone secretion from the gastrointestinal tract and pancreas, and regulate lipid and/or glucose metabolism in adipose, liver, and muscle tissues. Additionally, GPR120 is postulated to mediate anti-inflammatory and insulin-sensitizing effects in adipose and macrophages. These benefits suggest that GPR120 agonists have the potential to be an effective treatment for obesity, type 2 diabetes mellitus (T2DM), and other metabolic syndromes.

Area Covered: This article highlights and reviews research advances in this field that have been published in patent literature and peer-reviewed journals since 2014.

Expert Opinion: Current development has been hindered by species differences in GPR120 distribution, differences in GPR120-mediated signaling in distinct tissue types, and lack of available ligands with suitable selectivity for GPR120 over GPR40 in both human and rodents. The discovery of β-arrestin biased GPR120 agonists will help elucidate the potential of selective therapeutics that may discriminate between desirable and undesirable pharmacological effects.

Abbreviations: ALA: α-linolenic acid; AUC: area under the curve; BRET: bioluminescence resonance energy transfer; CCK: cholecystokinin; CHO-K1 cell: Chinese hamster ovary-K1 cell; mouse: diabetic mouse; DHA: docosahexaenoic acid; DIO: diet-induced obesity; DMSO: dimethyl sulfoxide; DPP-4: dipeptidyl peptidase 4; EPA: eicosapentaenoic acid; FA(s): fatty acid(s); FFA(s): free fatty acid(s); FFAR: free fatty acid receptor; FLIPR: fluorescent imaging plate reader; GIR: glucose infusion rate; GLP-1: glucagon-like peptide 1; GP(C)R: G protein-coupled receptor; GSIS: glucose-stimulated insulin secretion; HEK293 cell: human embryonic kidney 293 cell; HOMA-IR: homeostatic measurement assessment of insulin resistance; IP1: inositol phosphate turnover; IPGTT: intraperitoneal glucose tolerance test; LCFA(s): long-chain fatty acid(s); MED: maximal efficacy; MIN6 cell: mouse insulin-secreting cell; NPY: neuropeptide Y; OGTT: oral glucose tolerance test; pERK: phosphorylated ERK; PPAR: peroxisome proliferator-activated receptor; QD: once daily; SAR: structure-activity relationship; siRNA: small interfering ribonucleic acid; STC-1: intestinal secretin tumor cell; T2DM: type 2 diabetes mellitus; U2OS cell: human bone osteosarcoma epithelial cell; uHTS: ultrahigh-throughput screening; ZDF: zucker diabetic fatty.
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http://dx.doi.org/10.1080/13543776.2020.1811852DOI Listing
October 2020

The discovery of azetidine-piperazine di-amides as potent, selective and reversible monoacylglycerol lipase (MAGL) inhibitors.

Bioorg Med Chem Lett 2020 07 7;30(14):127243. Epub 2020 May 7.

Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA.

Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain.
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http://dx.doi.org/10.1016/j.bmcl.2020.127243DOI Listing
July 2020

The discovery of diazetidinyl diamides as potent and reversible inhibitors of monoacylglycerol lipase (MAGL).

Bioorg Med Chem Lett 2020 06 18;30(12):127198. Epub 2020 Apr 18.

Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA.

Monoacylglycerol lipase (MAGL) has emerged as an attractive drug target because of its important role in regulating the endocannabinoid 2-arachidonoylglycerol (2-AG) and its hydrolysis product arachidonic acid (AA) in the brain. Herein, we report the discovery of a novel series of diazetidinyl diamide compounds 6 and 10 as potent reversible MAGL inhibitors. In addition to demonstrating potent MAGL inhibitory activity in the enzyme assay, the thiazole substituted diazetidinyl diamides 6d-l and compounds 10 were also effective at increasing 2-AG levels in a brain 2-AG accumulation assay in homogenized rat brain. Furthermore, selected compounds have been shown to achieve good brain penetration after oral administration in an animal study.
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http://dx.doi.org/10.1016/j.bmcl.2020.127198DOI Listing
June 2020

Pharmacologic Characterization of JNJ-42226314, [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone, a Reversible, Selective, and Potent Monoacylglycerol Lipase Inhibitor.

J Pharmacol Exp Ther 2020 03 9;372(3):339-353. Epub 2019 Dec 9.

Janssen Research & Development, LLC, San Diego, California.

The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors (CBs) CB1 and CB2. Activation of these receptors has demonstrated beneficial effects on mood, appetite, pain, and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the pharmacologic characterization of [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone (JNJ-42226314), a reversible and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels, and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund's adjuvant-induced radiant heat hypersensitivity and chronic constriction injury-induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Though 30 mg/kg induced hippocampal synaptic depression, altered sleep onset, and decreased electroencephalogram gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels, and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several central nervous system disorders. SIGNIFICANCE STATEMENT: Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain, and inflammation. [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone is presented in this report to be a novel, potent, selective, and reversible noncovalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain.
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http://dx.doi.org/10.1124/jpet.119.262139DOI Listing
March 2020

6-Benzhydryl-4-amino-quinolin-2-ones as Potent Cannabinoid Type 1 (CB) Receptor Inverse Agonists and Chemical Modifications for Peripheral Selectivity.

J Med Chem 2018 11 31;61(22):10276-10298. Epub 2018 Oct 31.

Janssen Research & Development , 1400 McKean Road , Spring House , Pennsylvania 19477-0776 , United States.

A novel series of 6-benzhydryl-4-amino-quinolin-2-ones was discovered as cannabinoid type 1 receptor (CBR) inverse agonists based on the high-throughput screening hit, compound 1a. Structure-activity relationships were studied to improve in vitro/in vivo pharmacology and restrict distribution to the peripheral circulation. We adopted several strategies such as increasing topological polar surface area, incorporating discrete polyethylene glycol side chains, and targeting P-glycoprotein (P-gp) to minimize access to the brain. Compound 6a is a P-gp substrate and a potent and highly selective CBR inverse agonist, demonstrating excellent in vivo metabolic stability and a low brain to plasma ratio. However, brain receptor occupancy studies showed that compound 6a may accumulate in brain with repeat dosing. This was evidenced by compound 6a inhibiting food intake and inducing weight loss in diet-induced obese mice. Thus, a strategy based on P-gp efflux may not be adequate for peripheral restriction of the disclosed quinolinone series.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01467DOI Listing
November 2018

Tetrahydroindazole derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists.

Bioorg Med Chem Lett 2016 11 10;26(21):5346-5349. Epub 2016 Sep 10.

Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA(†).

A series of potent and receptor-selective cannabinoid-1 (CB1) receptor inverse agonists has been discovered. Peripheral selectivity of the compounds was assessed by a mouse tissue distribution study, in which the concentrations of a test compound in both plasma and brain were measured. A number of peripherally selective compounds have been identified through this process. Compound 2p was further evaluated in a 3-week efficacy study in the diet-induced obesity (DIO) mouse model. Beneficial effects on plasma glucose were observed from the compound-treated mice.
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http://dx.doi.org/10.1016/j.bmcl.2016.09.025DOI Listing
November 2016

Tetrahydropyrazolo[4,3-c]pyridine derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists.

Bioorg Med Chem Lett 2016 11 12;26(22):5597-5601. Epub 2016 Sep 12.

Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA(†).

Peripherally restricted CB1 receptor inverse agonists hold potential as useful therapeutics to treat obesity and related metabolic diseases without causing undesired CNS-mediated adverse effects. We identified a series of tetrahydropyrazolo[4,3-c]pyridine derivatives as potent and highly peripherally selective CB1 receptor inverse agonists. This discovery was achieved by introducing polar functional groups into the molecule, which increase the topological polar surface area and reduce its brain-penetrating ability.
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http://dx.doi.org/10.1016/j.bmcl.2016.09.026DOI Listing
November 2016

7-(4-Alkylidenylpiperidinyl)-quinolone bacterial topoisomerase inhibitors.

Bioorg Med Chem Lett 2014 Dec 12;24(23):5502-6. Epub 2014 Oct 12.

Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA.

Novel antibacterial fluoroquinolone agents bearing a 4-alkylidenylpiperidine 7-position substituent are active against quinolone-susceptible and quinolone-resistant gram-positive bacteria, including Streptococcus pneumoniae and MRSA. Analogs 22b, 23c, and 24 demonstrated superior in vitro and in vivo efficacy to ciprofloxacin against these cocci.
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http://dx.doi.org/10.1016/j.bmcl.2014.10.014DOI Listing
December 2014

Arylglycine derivatives as potent transient receptor potential melastatin 8 (TRPM8) antagonists.

Bioorg Med Chem Lett 2013 Apr 4;23(7):2234-7. Epub 2013 Feb 4.

Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA.

A series of arylglycine-based analogs was synthesized and tested for TRPM8 antagonism in a cell-based functional assay. Following structure-activity relationship studies in vitro, a number of compounds were identified as potent TRPM8 antagonists and were subsequently evaluated in an in vivo pharmacodynamic assay of icilin-induced 'wet-dog' shaking in which compound 12 was fully effective. TRPM8 antagonists of the type described here may be useful in treating pain conditions wherein cold hypersensitivity is a dominant feature.
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http://dx.doi.org/10.1016/j.bmcl.2013.01.062DOI Listing
April 2013

Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 Å resolution.

Protein Sci 2011 Apr 1;20(4):670-83. Epub 2011 Mar 1.

Department of Structural Biology, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, Spring House, Pennsylvania 19477, USA.

A high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase (MGL) is presented. The structure highlights a novel conformation of the regulatory lid-domain present in the lipase family as well as the binding mode of a pharmaceutically relevant reversible inhibitor. Analysis of the structure lacking the inhibitor indicates that the closed conformation can accommodate the native substrate 2-arachidonoyl glycerol. A model is proposed in which MGL undergoes conformational and electrostatic changes during the catalytic cycle ultimately resulting in its dissociation from the membrane upon completion of the cycle. In addition, the study outlines a successful approach to transform membrane associated proteins, which tend to aggregate upon purification, into a monomeric and soluble form.
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http://dx.doi.org/10.1002/pro.596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081545PMC
April 2011

New β-lactam antibiotics and β-lactamase inhibitors.

Expert Opin Ther Pat 2010 Oct;20(10):1277-93

Indiana University, Biology Department, Bloomington, IN 47405, USA.

Importance Of The Field: β-Lactam antibiotics are among the most frequently prescribed antibiotics used to treat bacterial infections. However, their utility is being threatened by the worldwide proliferation of β-lactamases with broad hydrolytic capabilities, especially in multidrug-resistant Gram-negative bacteria.

Areas Covered In This Review: This review describes new β-lactams and β-lactamase inhibitors described in the patent literature primarily between 2007 and 2010, together with supportive meeting abstracts and relevant descriptive literature.

What The Reader Will Gain: Readers will learn which classes of β-lactam antibiotics are being explored as the most promising groups of compounds to counteract resistance in Gram-negative pathogenic bacteria. Somewhat surprisingly, few traditional β-lactam classes such as penicillins or cephalosporins were described in the literature, other than in combinations with other β-lactams or β-lactamase inhibitors that are being developed to inhibit enzymes from all molecular classes.

Take Home Message: β-Lactam antibiotics are currently being developed as monotherapy by only a few companies. The major emphasis in the past 4 years has been the discovery of novel β-lactamase inhibitors or inhibitor combinations that will allow use of β-lactams against multidrug-resistant bacteria. The use of β-lactams as single agents appears to be a limited option for the future.
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http://dx.doi.org/10.1517/13543776.2010.515588DOI Listing
October 2010

In vitro antibacterial activities of JNJ-Q2, a new broad-spectrum fluoroquinolone.

Antimicrob Agents Chemother 2010 May 22;54(5):1955-64. Epub 2010 Feb 22.

Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ 08869, USA.

JNJ-Q2, a novel fluorinated 4-quinolone, was evaluated for its antibacterial potency by broth and agar microdilution MIC methods in studies focused on skin and respiratory tract pathogens, including strains exhibiting contemporary fluoroquinolone resistance phenotypes. Against a set of 118 recent clinical isolates of Streptococcus pneumoniae, including fluoroquinolone-resistant variants bearing multiple DNA topoisomerase target mutations, an MIC(90) value for JNJ-Q2 of 0.12 microg/ml was determined, indicating that it was 32-fold more potent than moxifloxacin. Against a collection of 345 recently collected methicillin-resistant Staphylococcus aureus (MRSA) isolates, including 256 ciprofloxacin-resistant strains, the JNJ-Q2 MIC(90) value was 0.25 microg/ml, similarly indicating that it was 32-fold more potent than moxifloxacin. The activities of JNJ-Q2 against Gram-negative pathogens were generally comparable to those of moxifloxacin. In further studies, JNJ-Q2 exhibited bactericidal activities at 2x and 4x MIC levels against clinical isolates of S. pneumoniae and MRSA with various fluoroquinolone susceptibilities, and its activities were enhanced over those of moxifloxacin. In these studies, the activity exhibited against strains bearing gyrA, parC, or gyrA plus parC mutations was indicative of the relatively balanced (equipotent) activity of JNJ-Q2 against the DNA topoisomerase target enzymes. Finally, determination of the relative rates or frequencies of the spontaneous development of resistance to JNJ-Q2 at 2x and 4x MICs in S. pneumoniae, MRSA, and Escherichia coli were indicative of a lower potential for resistance development than that for current fluoroquinolones. In conclusion, JNJ-Q2 exhibits a range of antibacterial activities in vitro that is supportive of its further evaluation as a potential new agent for the treatment of skin and respiratory tract infections.
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http://dx.doi.org/10.1128/AAC.01374-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2863672PMC
May 2010

Synthesis and antibacterial activity of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones.

Bioorg Med Chem Lett 2009 Sep 22;19(17):4933-6. Epub 2009 Jul 22.

Research & Early Development, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Welsh and McKean Roads, Spring House, PA 19477, USA.

A novel series of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones has been designed and synthesized in which the heterocyclic side chain is attached to the quinolone core through a carbon-carbon linkage. The antibacterial activity of the compounds was determined against a panel of Gram-positive and Gram-negative pathogens. Compounds 1b and 1e, bearing an 8-methoxy group as well as unsubstituted and (3S)-methyl substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl side chains, respectively, demonstrated notable activity against ciprofloxacin-resistant clinical isolates of Streptococcus pneumoniae.
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http://dx.doi.org/10.1016/j.bmcl.2009.07.087DOI Listing
September 2009

In vivo activity of the pyrrolopyrazolyl-substituted oxazolidinone RWJ-416457.

Antimicrob Agents Chemother 2009 May 9;53(5):2028-33. Epub 2009 Mar 9.

Johnson & Johnson Pharmaceutical Research and Development, 1000 Route 202, Raritan, NJ 08869, USA.

RWJ-416457 is an investigational pyrrolopyrazolyl-substituted oxazolidinone with activity against antibiotic-susceptible and -resistant gram-positive pathogens. Efficacies of RWJ-416457, linezolid, and vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA) and community-associated methicillin-resistant S. aureus (CA-MRSA) in murine skin and systemic infections were compared, as were efficacies against Streptococcus pneumoniae in a lower respiratory infection. In staphylococcal systemic infections, RWJ-416457 was equipotent with to twofold more potent than linezolid, with 50% effective dose values ranging from 1.5 to 5 mg/kg of body weight/day. RWJ-416457 was two- to fourfold less potent than vancomycin against MSSA but up to fourfold more potent than vancomycin against CA-MRSA. In MSSA and CA-MRSA skin infections, RWJ-416457 demonstrated an efficacy similar to that of linezolid, reducing CFU/g skin approximately 1.0 log(10) at all doses tested; vancomycin yielded greater reductions than the oxazolidinones, with decreases in CFU/g skin of 3 log(10) (MSSA) and 2 log(10) (CA-MRSA). In the pneumococcal model, RWJ-416457 was two- to fourfold more potent than linezolid. The free-drug area under the concentration-time curves at 24 h (fAUC(24)) were similar for RWJ-416457 and linezolid. The half-life of RWJ-416457 was up to threefold longer than that of linezolid for all routes of administration. The fAUC(24)/MIC ratio, the pharmacodynamic parameter considered predictive of oxazolidinone efficacy, was approximately twofold greater for RWJ-416457 than for linezolid. Since the fAUC values were similar for both compounds, the higher fAUC/MIC ratios of RWJ-416457 appear to result from its greater in vitro potency. These results demonstrate that RWJ-416457 is a promising new oxazolidinone with efficacy in S. aureus or S. pneumoniae mouse infection models.
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http://dx.doi.org/10.1128/AAC.00833-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681548PMC
May 2009

Synthesis and antibacterial activity of 3-keto-6-O-carbamoyl-11,12-cyclic thiocarbamate erythromycin A derivatives.

Bioorg Med Chem Lett 2007 Jul 3;17(14):3900-4. Epub 2007 May 3.

Research & Early Development, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 8 Clarke Drive, Cranbury, NJ 08512, USA.

A series of 3-keto-6-O-carbamoyl-11,12-cyclic thiocarbamate erythromycin A derivatives has been synthesized. The best compounds in this series possess potent in vitro antibacterial activity against erythromycin-susceptible and erythromycin-resistant bacteria.
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http://dx.doi.org/10.1016/j.bmcl.2007.04.104DOI Listing
July 2007

Anti-MRSA beta-lactams in development, with a focus on ceftobiprole: the first anti-MRSA beta-lactam to demonstrate clinical efficacy.

Expert Opin Investig Drugs 2007 Apr;16(4):419-29

Johnson & Johnson Pharmaceutical Research & Development L.L.C., Raritan, NJ, USA.

Ceftobiprole is the first of the investigational beta-lactam antibiotics with in vitro activity against methicillin-resistant staphylococci to reach and complete Phase III therapeutic trials. Its antibacterial spectrum includes methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, penicillin-resistant streptococci and many Gram-negative pathogens. It has demonstrated in vivo activity against many experimental infections caused by these pathogens. Ceftobiprole has completed Phase III clinical trials for complicated skin and skin structure infections, is being studied in Phase III pneumonia trials and has demonstrated non-inferiority compared with vancomycin in a Phase III complicated skin and skin structure infections trial, resulting in > 90% clinical cures of infections caused by MRSA. Other anti-MRSA beta-lactams in therapeutic clinical trials include the carbapenem CS-023/RO-4908463 and the cephalosporin ceftaroline (PPI-0903). The future of all of these agents will depend on their clinical efficacy, safety and their ability to be accepted as beta-lactams for the reliable treatment of a broad spectrum of infections, including those caused by MRSA.
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http://dx.doi.org/10.1517/13543784.16.4.419DOI Listing
April 2007

In vitro antibacterial activity of the pyrrolopyrazolyl-substituted oxazolidinone RWJ-416457.

Antimicrob Agents Chemother 2007 Jan 13;51(1):361-5. Epub 2006 Nov 13.

Johnson and Johnson Pharmaceutical Research and Development, L.L.C., Raritan, NJ 08869, USA.

RWJ-416457, an investigational pyrrolopyrazolyl-substituted oxazolidinone, inhibited the growth of linezolid-susceptible staphylococci, enterococci, and streptococci at concentrations of < or =4 microg/ml, generally exhibiting two- to fourfold-greater potency than that of linezolid. Time-kill studies demonstrated bacteriostatic effects for both RWJ-416457 and linezolid.
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http://dx.doi.org/10.1128/AAC.01017-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797661PMC
January 2007

Synthesis and antibacterial activity of C6-carbazate ketolides.

Bioorg Med Chem Lett 2006 Dec 25;16(24):6231-5. Epub 2006 Sep 25.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C, 1000 Route 202, PO Box 300, Raritan, NJ 08869, USA.

A novel series of ketolides containing heteroaryl groups that are linked to the erythronolide ring via a C6-carbazate functionality has been successfully synthesized. Careful modulation of the heteroaryl groups, the length and degree of saturation of the C6-carbazate linker, and the substituents present on each of the carbazate nitrogens led to compounds with potent activity against key bacterial respiratory pathogens. The best analogs of this series had in vitro and in vivo (sc dosing) profiles that were comparable to telithromycin.
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http://dx.doi.org/10.1016/j.bmcl.2006.09.036DOI Listing
December 2006

Antibacterial activity of pyrrolopyridine-substituted oxazolidinones: synthesis and in vitro SAR of various C-5 acetamide replacements.

Bioorg Med Chem Lett 2006 Sep 27;16(17):4537-42. Epub 2006 Jun 27.

Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ 08869, USA.

A series of pyrrolopyridine-substituted oxazolidinones containing various C-5 acetamide isosteres was synthesized and the structure-antibacterial activity relationships determined against a representative panel of susceptible and resistant Gram-positive bacteria.
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http://dx.doi.org/10.1016/j.bmcl.2006.06.023DOI Listing
September 2006

Synthesis and antibacterial activity of 6-O-heteroarylcarbamoyl-11,12-lactoketolides.

Bioorg Med Chem Lett 2006 Apr 30;16(7):1929-33. Epub 2006 Jan 30.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, PO Box 300, Raritan, NJ 08869, USA.

A new series of erythromycin A derivatives, the 6-O-heteroarylcarbamoyl-11,12-lactoketolides, with activity against macrolide-resistant streptococci, are described. Structurally, these macrolide antibiotics are characterized by a heteroaryl side chain attached to the macrolactone core through a carbamate linkage at the C6 position, as well as 11,12-gamma-lactone and 3-keto functionalities. The synthesis and antibacterial activity of this new series of ketolides are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2005.12.097DOI Listing
April 2006

Synthesis and antibacterial activity of 3-O-acyl-6-O-carbamoyl erythromycin A derivatives.

Bioorg Med Chem Lett 2006 Feb 11;16(4):1054-9. Epub 2005 Nov 11.

Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C. 1000 Route 202, PO Box 300, Raritan, NJ 08869, USA.

A series of 3-O-acyl-6-O-carbamoyl erythromycin A derivatives has been synthesized. Several functional groups were identified as the optimal C3-substituents, and the best compounds in this series possess potent in vitro antibacterial activity against erythromycin-susceptible and erythromycin-resistant bacteria.
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http://dx.doi.org/10.1016/j.bmcl.2005.10.074DOI Listing
February 2006

Pyrroloquinolone PDE5 inhibitors with improved pharmaceutical profiles for clinical studies on erectile dysfunction.

J Med Chem 2005 Mar;48(6):2126-33

Johnson & Johnson Pharmaceutical Research and Development, 1000 Route 202, Raritan, New Jersey 08869, USA.

We previously reported a series of potent and selective pyrimidinyl pyrroloquinolone PDE5 inhibitors such as 2a for potential use in male erectile dysfunction (MED) (Sui, Z.; Guan, J.; Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P., Bhattacharjee, S.; John, T. M.; Craig, E.; Haynes-Johnson, D.; Clancy, J. J. Med. Chem. 2002, 45, 4094-4096). Unfortunately, the low aqueous solubility and poor oral bioavailability rendered them undesirable development candidates. To address this issue, we designed a series of analogues using two approaches: increasing the overall basicity and reducing molecular weight of the lead. Through earlier SAR studies, we discovered that the PDE5 potency of the pyrroloquinolones is insensitive to substitution on the pyrrole nitrogen. Basic functional groups such as pyridines and benzimidazoles were appended via the aromatic ring connected to the pyrrole nitrogen. Several truncated analogues were also designed and synthesized to improve oral absorption. These modifications allowed us to identify analogues with good oral bioavailability in rats, dogs, and monkeys while the high potency against PDE5 and desirable selectivity versus other PDE isozymes were maintained. Compounds R-11e and R-11l were selected as development candidates for MED and other indications.
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http://dx.doi.org/10.1021/jm0401098DOI Listing
March 2005

Synthesis and antibacterial activity of C-6 carbamate ketolides, a novel series of orally active ketolide antibiotics.

Bioorg Med Chem Lett 2004 Sep;14(17):4495-9

Johnson & Johnson Pharmaceutical Research & Development, LLC, 1000 Route 202, PO Box 300, Raritan, NJ 08869, USA.

A new series of antibacterial ketolides is reported, which features the use of a C-6 carbamate for tethering the arylalkyl sidechain to the macrolide core. The best members of this series display in vitro and in vivo activity comparable to telithromycin. Partial epimerization at C-2, unobserved in previously reported ketolides, was noted for this series.
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http://dx.doi.org/10.1016/j.bmcl.2004.06.045DOI Listing
September 2004

The synthesis and antimicrobial evaluation of a new series of isoxazolinyl oxazolidinones.

Bioorg Med Chem Lett 2004 Jun;14(12):3069-72

Antimicrobial Agents Research Team, Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, LL C, 1000 Route 202, Raritan, NJ 08869, USA.

A series of oxazolidinone antibacterial agents containing a 5-substituted isoxazol-3-yl moiety were synthesized via a nitrile oxide [3+2] dipolar cycloaddition reaction. These compounds were screened against a panel of susceptible and resistant Gram-positive organisms. Several analogs from this series were comparable to or more potent than linezolid in vitro.
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http://dx.doi.org/10.1016/j.bmcl.2004.04.037DOI Listing
June 2004

Structure-activity relationships of N-acyl pyrroloquinolone PDE-5 inhibitors.

J Med Chem 2004 Jan;47(3):656-62

Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development LLC, 1000 Route 202 S, P.O. Box 300, Raritan, New Jersey 08869, USA.

The discovery of the potent and selective PDE-5 inhibitory activity of a pyrroloquinolone scaffold prompted us to explore the SAR of its acyl derivatives. During the course of these studies, three structural series were found with K(i) values for PDE-5 in the subnanomolar range. Systematic modification of one of these leads produced a compound with excellent selectivity for PDE-5 over other phosphodiesterases and oral bioavailability of 15% in male rats. This compound also displayed in vivo efficacy in an anesthetized canine model of erection when dosed intravenously.
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http://dx.doi.org/10.1021/jm020521sDOI Listing
January 2004

Synthesis and antibacterial activity of pyrroloaryl-substituted oxazolidinones.

Bioorg Med Chem Lett 2003 Dec;13(23):4173-7

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Route 202, PO Box 300, Raritan, NJ 08869, USA.

A novel series of oxazolidinones containing a pyrroloaryl substituent was synthesized and screened against a representative panel of susceptible and resistant Gram-positive bacteria. Several members of this series were found to have antibacterial activity comparable to or better than linezolid.
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http://dx.doi.org/10.1016/j.bmcl.2003.08.031DOI Listing
December 2003

Synthesis and biological activities of novel beta-carbolines as PDE5 inhibitors.

Bioorg Med Chem Lett 2003 Feb;13(4):761-5

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 1000 Route 202, Raritan, NJ 08869, USA.

A series of N(2)-furoyl and N(2)pyrimidinyl beta-carbolines was discovered to possess potent inhibitory activity against PDE5. During the synthesis we developed a tandem resin quenching protocol, which allowed us to synthesize large number of target compounds in a rapid fashion. Representative compounds exhibit superior selectivity to sildenafil versus other isozymes of PDEs, and demonstrated in vivo efficacy in increasing introcavernosal pressure in dogs.
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http://dx.doi.org/10.1016/s0960-894x(02)01036-3DOI Listing
February 2003

Furoyl and benzofuroyl pyrroloquinolones as potent and selective PDE5 inhibitors for treatment of erectile dysfunction.

J Med Chem 2003 Jan;46(3):441-4

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 1000 Route 202 South, P.O. Box 300, Raritan, New Jersey 08869, USA.

Synthesis of furoyl and benzofuroyl pyrroloquinolones as potent and selective PDE5 inhibitors was reported. Their in vitro potencies in inhibiting PDE5 and selectivity in inhibiting other PDE isozymes (PDE1-4 and PDE6) were evaluated. Some of these compounds are more potent than sildenafil with better selectivity toward PDE1 and PDE6. Incorporation of solublizing groups resulted in bioavailable analogues. Selected compounds showed in vivo efficacy in anesthetized dog model for penile erection.
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http://dx.doi.org/10.1021/jm0202573DOI Listing
January 2003

Pyrimidinylpyrroloquinolones as highly potent and selective PDE5 inhibitors for treatment of erectile dysfunction.

J Med Chem 2002 Sep;45(19):4094-6

Johnson & Johnson Pharmaceutical Research & Development, Drug Discovery, 1000 Route 202, Raritan, NJ 08869, USA.

A series of N-pyrimidinylpyrroloquinolones were discovered as extremely potent and selective PDE5 inhibitors. Representative compounds demonstrated in vivo efficacy in dog erectile dysfunction models and are orally bioavailable.
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http://dx.doi.org/10.1021/jm025545dDOI Listing
September 2002