11,123 results match your criteria potent orally

MC-100093, a novel β-lactam GLT-1 enhancer devoid of antimicrobial properties attenuates cocaine relapse in rats.

J Pharmacol Exp Ther 2021 May 13. Epub 2021 May 13.

School of Pharmacy, Temple University, United States.

Cocaine use disorder (CUD) currently lacks FDA-approved treatments. In rodents, the glutamate transporter-1 (GLT-1) is downregulated in the nucleus accumbens following cocaine self-administration and increasing the expression and function of GLT-1 reduces the reinstatement of cocaine-seeking. The beta-lactam antibiotic ceftriaxone upregulates GLT-1 and attenuates cue- and cocaine-induced cocaine seeking without affecting motivation for natural rewards. Read More

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Biased action of the CXCR4-targeting drug plerixafor is essential for its superior hematopoietic stem cell mobilization.

Commun Biol 2021 May 12;4(1):569. Epub 2021 May 12.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.

Following the FDA-approval of the hematopoietic stem cell (HSC) mobilizer plerixafor, orally available and potent CXCR4 antagonists were pursued. One such proposition was AMD11070, which was orally active and had superior antagonism in vitro; however, it did not appear as effective for HSC mobilization in vivo. Here we show that while AMD11070 acts as a full antagonist, plerixafor acts biased by stimulating β-arrestin recruitment while fully antagonizing G protein. Read More

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Acute toxicity analysis of an inhibitor of BCL2, Disarib, in rats.

Sci Rep 2021 May 11;11(1):9982. Epub 2021 May 11.

Institute of Bioinformatics and Applied Biotechnology, Electronics City, Bangalore, 560100, India.

Apoptosis or programmed cell death is a highly regulated process, which eliminates unwanted and damaged cells. Inhibition of apoptosis is a hallmark of cancer cells. BCL2 family proteins are known to play a vital role in the regulation of apoptosis. Read More

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Novel hybrid conjugates with dual estrogen receptor α degradation and histone deacetylase inhibitory activities for breast cancer therapy.

Bioorg Med Chem 2021 May 1;40:116185. Epub 2021 May 1.

Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address:

Hormone therapy targeting estrogen receptors is widely used clinically for the treatment of breast cancer, such as tamoxifen, but most of them are partial agonists, which can cause serious side effects after long-term use. The use of selective estrogen receptor down-regulators (SERDs) may be an effective alternative to breast cancer therapy by directly degrading ERα protein to shut down ERα signaling. However, the solely clinically used SERD fulvestrant, is low orally bioavailable and requires intravenous injection, which severely limits its clinical application. Read More

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DBPR108, a novel dipeptidyl peptidase-4 inhibitor with antihyperglycemic activity.

Life Sci 2021 May 5;278:119574. Epub 2021 May 5.

Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan. Electronic address:

Aims: Dipeptidyl peptidase 4 (DPP-4) is a valid molecular drug target from which its inhibitors have been developed as medicines for treating diabetes. The present study evaluated a new synthetic DPP-4-specific inhibitor of small molecule DBPR108 for pharmacology and pharmacokinetic profiles.

Main Methods: DBPR108 of various doses was orally administered to rats, diabetic mice, and dogs and the systemic circulating DPP-4 activities in the animals were measured to demonstrate the pharmacological mechanisms of action via DPP-4 inhibition. Read More

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Anti-hypersensitivity effect of betanin (red beetroot extract) via modulation of microglial activation in a mouse model of neuropathic pain.

Eur J Pain 2021 May 7. Epub 2021 May 7.

Department of Functional Anatomy, Graduate School of Medical Science, Kanazawa University, Japan.

Background: Neuropathic pain (NeP) medications have several side effects that affect NeP patients' quality of life. Betanin, the most common betacyanin pigment, has been shown to have potent antioxidant and anti-inflammatory properties in vivo; thus, it has potential as a healthcare treatment. In this study, we focused on betanin (red beetroot extract) as a potential therapy for NeP. Read More

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Covid-19 Community Mitigation Status at Selected Districts of Southwest Ethiopia: A Mixed Design Survey.

Risk Manag Healthc Policy 2021 28;14:1763-1775. Epub 2021 Apr 28.

Health Education in School of Public Health, College of Medicine and Health Sciences, Nech Sar Campus, Arba Minch University, Arba Minch, Southwest Ethiopia, Ethiopia.

Background: The spread of covid-19 was alarmingly continued in Ethiopia. This survey assessed the status of community mitigations to fight the pandemic. The ongoing forward effort by local task forces can be assessed to note the achievements. Read More

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Gallic acid treats dust-induced NAFLD in rats by improving the liver's anti-oxidant capacity and inhibiting ROS/NFκβ/TNFα inflammatory pathway.

Iran J Basic Med Sci 2021 Feb;24(2):240-247

Cellular and Molecular Research Center, Department of Anatomical Science, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Objectives: The burden of disease and death related to environmental pollution is becoming a major public health challenge, especially in developing countries. This study was designed to investigate the effect of dust exposure on liver function and its structure in rats. Gallic acid (GA) as a potent anti-oxidant was also used to treat NAFLD in rats exposed to dust. Read More

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February 2021

Modulator effect of mangiferin on biochemical characterization in 7,12-dimethylbenz[a]anthracene induced oral cancer in experimental hamsters.

Vet Med Sci 2021 May 5. Epub 2021 May 5.

Department of Intensive Care Medicine, Qingdao Municipal Hospital, Qingdao, China.

Background: Newly, chemo-preventive technique might be a hopeful advancement in developing countries for treating cancers with the aid of toxic less natural based constituents. Malignancy urges to augment effectual chemo-preventive agents that are look forward to suppress the tumours which may be stimulated by chewing and smoking of tobacco and over alcohol consumption related with the high prevalence of human oral cancer (OC) patients.

Methods: In the present research, we examined to assess antioxidants, lipid peroxidation (LPO) and detoxification enzymes levels of anticancer activity of mangiferin on 0. Read More

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Preclinical development and first in human study of KA2507, a selective and potent inhibitor of histone deacetylase 6, for patients with refractory solid tumors.

Clin Cancer Res 2021 May 4. Epub 2021 May 4.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center.

Purpose: Inhibition of histone deacetylase 6 (HDAC6) is predicted to deliver both direct antitumor activity and modulation of the antitumor immune response. This study describes the development of a novel HDAC6 inhibitor.

Patients And Methods: KA2507 was characterized in HDAC biochemical and cellular target engagement assays and in preclinical efficacy models of melanoma and colorectal cancer. Read More

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Effects of TGF-β1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells.

Int J Mol Sci 2021 Apr 29;22(9). Epub 2021 Apr 29.

Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Korea.

We investigated the effectiveness of the transforming growth factor beta-1 (TGF-β) receptor inhibitor GW788388 on the epithelial to mesenchymal transition (EMT) using human peritoneal mesothelial cells (HPMCs) and examined the effectiveness of GW788388 on the peritoneal membrane using a peritoneal fibrosis mouse model. HPMCs were treated with TGF-β with or without GW788388. Animal experiments were conducted on male C57/BL6 mice. Read More

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X-ray Crystal Structure-Guided Design and Optimization of 7-Pyrrolo[2,3-]pyrimidine-5-carbonitrile Scaffold as a Potent and Orally Active Monopolar Spindle 1 Inhibitor.

J Med Chem 2021 May 4. Epub 2021 May 4.

College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, South Korea.

Triple-negative breast cancer (TNBC) is an aggressive breast-cancer subtype associated with poor prognosis and high relapse rates. Monopolar spindle 1 kinase (MPS1) is an apical dual-specificity protein kinase that is over-expressed in TNBC. We herein report a highly selective MPS1 inhibitor based on a 7-pyrrolo[2,3-]pyrimidine-5-carbonitrile scaffold. Read More

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Mirogabalin, a novel ligand for αδ subunit of voltage-gated calcium channels, improves cognitive impairments in repeated intramuscular acidic saline injection model rats, an experimental model of fibromyalgia.

Biomed Pharmacother 2021 Apr 30;139:111647. Epub 2021 Apr 30.

Specialty Medicine Research Laboratories I, Daiichi-Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address:

Mirogabalin is a novel potent and selective ligand for the αδ subunit of voltage-gated calcium channels, and shows potent and sustained analgesic effects in neuropathic pain and fibromyalgia models. Fibromyalgia is often associated with multiple comorbid symptoms, such as anxiety, depression and cognitive impairment. In the present study, we investigated the effects of mirogabalin on cognitive impairments in an experimental animal model for fibromyalgia, repeated intramuscular acidic saline injection model (Sluka model) rats. Read More

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Behavioural effects in mice orally exposed to domoic acid or ibotenic acid are influenced by developmental stages and sex differences.

Biochem Biophys Res Commun 2021 Jun 28;558:175-182. Epub 2021 Apr 28.

Laboratory of Animal Reproduction and Development, Graduate School of Agricultural, Science, Tohoku University, 468-1 Aramaki-Aoba, Aoba-ku, Sendai, Miyagi, 980-8572, Japan. Electronic address:

The structure of the brain is dramatically altered during the critical period. Physiological substances (neurotransmitters, hormones, etc.) in the body fluctuate significantly before and after sexual maturation. Read More

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Calcitonin gene-related peptide (CGRP) receptor antagonists: Heterocyclic modification of a novel azepinone lead.

Bioorg Med Chem Lett 2021 Apr 29;43:128077. Epub 2021 Apr 29.

Bristol-Myers Squibb, Wallingford, CT 06492, United States; Biohaven Pharmaceuticals Inc., New Haven, CT 06510, United States.

In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-dependent human CYP3A4 inhibition. Through heterocyclic replacement of the indazole ring, we discovered a series of heterocycle derivatives as high-affinity CGRP receptor antagonists. Some of them showed reasonable oral exposures, and the imidazolone derivatives that showed good oral exposure also exhibited substantially reduced time-dependent CYP3A4 inhibition. Read More

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Emerging approaches to male contraception.

Fertil Steril 2021 Apr 27. Epub 2021 Apr 27.

Center for Research in Reproduction and Contraception, Department of Medicine, University of Washington, Seattle, Washington. Electronic address:

Despite significant interests in contraception by men, effective methods of male contraception are limited to vasectomy and condoms. Recently, there have been several promising advances in male contraceptive research. This review will update readers on recent research in both hormonal and nonhormonal approaches to male contraception. Read More

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A Phase I Study of an IDO-1 Inhibitor (LY3381916) as Monotherapy and in Combination With an Anti-PD-L1 Antibody (LY3300054) in Patients With Advanced Cancer.

J Immunother 2021 Apr 28. Epub 2021 Apr 28.

Jules Bordet Institute, Brussels University Hospital Antwerp, Edegem, Belgium Drug Development Department (DITEP), Gustave Roussy Institute, Villejuif, France Department of Hematology-Oncology, Indiana University Simon Comprehensive Cancer Center Eli Lilly and Company Indiana University School of Medicine, Indianapolis, IN Ghent University Hospital, Ghent, Belgium Eli Lilly and Company, New York, NY Eli Lilly and Company, Stockholm, Sweden Eli Lilly and Company, Surrey, UK Sarah Cannon Research Institute Tennessee Oncology, Nashville, TN.

LY3381916 is an orally available, highly selective, potent inhibitor of indoleamine 2,3-dioxygenase 1. This study explored the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of LY3381916 monotherapy and in combination with a programmed death-ligand 1 (PD-L1) inhibitor (LY3300054) in patients with advanced solid tumors. During dose escalation, patients received escalating doses of LY3381916 at 60-600 mg once daily (qd) and 240 mg twice daily in monotherapy (n=21) and in combination with PD-L1 inhibitor at 700 mg every 2 weeks (n=21). Read More

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A Targeted-Covalent Inhibitor of 17β-HSD1 Blocks Two Estrogen-Biosynthesis Pathways: In Vitro (Metabolism) and In Vivo (Xenograft) Studies in T-47D Breast Cancer Models.

Cancers (Basel) 2021 Apr 13;13(8). Epub 2021 Apr 13.

Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec-Research Center, Québec, QC G1V 4G2, Canada.

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) plays an important role in estrogen-dependent breast tumor growth. In addition to being involved in the production of estradiol (E2), the most potent estrogen in women, 17β-HSD1 is also responsible for the production of 5-androsten-3β,17β-diol (5-diol), a weaker estrogen than E2, but whose importance increases after menopause. 17β-HSD1 is therefore a target of choice for the treatment of estrogen-dependent diseases such as breast cancer and endometriosis. Read More

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A Preliminary Study on the Effect of Psyllium Husk Ethanolic Extract on Hyperlipidemia, Hyperglycemia, and Oxidative Stress Induced by Triton X-100 Injection in Rats.

Biology (Basel) 2021 Apr 16;10(4). Epub 2021 Apr 16.

Department of Biotechnology, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.

The aim of this study is to assess the efficiency of psyllium husk ethanolic extract (PHEE) on Triton X-100 induced hyperlipidemic rats by studying the changes in hepatic and pancreatic function and histopathology. Forty male albino rats (bodyweight 175-188 g) were grouped randomly into four sets with ten rats. The experimental groups included: (1) control group (CON); (2) Triton X-100 induced hyperlipidemic group-rats were intraperitoneally injected with a single dose of Triton X-100 (100 mg/kg body weight) on the 21st day of Trial onset; (3) PHEE group-PHEE was orally administered (100 mg/kg body weight dissolved in 1 mL of distilled water) by gastric tube from the first day of the experiment until the fortieth day, once daily, (PHEE); (4) PHEE +Triton group, which received PHEE orally with the induction of hyperlipidemia. Read More

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β-Sitosterol Circumvents Obesity Induced Inflammation and Insulin Resistance by down-Regulating IKKβ/NF-κB and JNK Signaling Pathway in Adipocytes of Type 2 Diabetic Rats.

Molecules 2021 Apr 6;26(7). Epub 2021 Apr 6.

Department of Anatomy, All India Institute of Medical Sciences, Nagpur, Maharashtra 440025, India.

β-sitosterol (SIT), the most abundant bioactive component of vegetable oil and other plants, is a highly potent antidiabetic drug. Our previous studies show that SIT controls hyperglycemia and insulin resistance by activating insulin receptor and glucose transporter 4 (GLUT-4) in the adipocytes of obesity induced type 2 diabetic rats. The current research was undertaken to investigate if SIT could also exert its antidiabetic effects by circumventing adipocyte induced inflammation, a key driving factor for insulin resistance in obese individuals. Read More

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Anti-Inflammatory and Anti-Hyperuricemic Effects of Chrysin on a High Fructose Corn Syrup-Induced Hyperuricemia Rat Model via the Amelioration of Urate Transporters and Inhibition of NLRP3 Inflammasome Signaling Pathway.

Antioxidants (Basel) 2021 Apr 6;10(4). Epub 2021 Apr 6.

Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan.

Hyperuricemia is the main cause of gout and involved in the occurrence of many other diseases such as hyperlipidemia and hypertension correlated with metabolic disorders. Chrysin is a flavonoid compound found naturally in honey, propolis, and mushrooms and has anti-inflammatory and antioxidant effects. However, its mechanism of action is not clear yet. Read More

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Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling.

Cancers (Basel) 2021 Apr 1;13(7). Epub 2021 Apr 1.

Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.

Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive disease with few therapeutic options. Hyperactive androgen receptor (AR) signaling plays a key role in CRPC progression. Previously, we identified RAR-related orphan receptor gamma (RORγ) as a novel key driver of AR gene overexpression and increased AR signaling. Read More

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Examination of the antiepileptic effects of valacyclovir using kindling mice- search for novel antiepileptic agents by drug repositioning using a large medical information database.

Eur J Pharmacol 2021 Apr 25;902:174099. Epub 2021 Apr 25.

Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences, Japan; Department of Pharmacy, Tokushima University Hospital, Japan.

Despite the availability of more than 20 clinical antiepileptic drugs, approximately 30% of patients with epilepsy do not respond to antiepileptic drug treatment. Therefore, it is important to develop antiepileptic products that function via novel mechanisms. In the present study, we evaluated data from one of the largest global databases to identify drugs with antiepileptic effects, and subsequently attempted to understand the effect of the combination of antiepileptic drugs and valacyclovir in epileptic seizures using a kindling model. Read More

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Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors.

Bioorg Med Chem Lett 2021 Apr 23;43:128058. Epub 2021 Apr 23.

HiberCell Inc. 619 West 54th Street, New York, NY 10019, USA. Electronic address:

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of the three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) that regulates protein synthesis, alleviates cellular ER stress and has been implicated in tumorigenesis and prolonged cancer cell survival. In this study, we report a series of 2-amino-3-amido-5-aryl-pyridines that we have identified as potent, selective, and orally bioavailable PERK inhibitors. Amongst the series studied herein, compound (28) a (R)-2-Amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-isopropylnicotinamide has demonstrated potent biochemical and cellular activity, robust pharmacokinetics and 70% oral bioavailability in mice. Read More

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Design, synthesis and molecular docking studies of thymol based 1,2,3-triazole hybrids as thymidylate synthase inhibitors and apoptosis inducers against breast cancer cells.

Bioorg Med Chem 2021 May 20;38:116136. Epub 2021 Apr 20.

Chemistry Department, Faculty of Applied Sciences, Umm Al-Qura University, Makkah, Saudi Arabia; Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia.

Natural product produced by plants has been the backbone for numerous anticancer agents. In the present work, natural bioactive thymol based 1,2,3-triazole hybrids have been synthesized and evaluated for anticancer activity in MCF-7 and MDA-MB-231 cancer cells. The synthesized molecules displayed desired pharmacokinetic predictions for an orally available drug. Read More

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Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis.

Nat Med 2021 Apr 22. Epub 2021 Apr 22.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2α. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Read More

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First-in-human study of the safety, pharmacokinetics, and pharmacodynamics of first-in-class fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors.

EClinicalMedicine 2021 Apr 30;34:100797. Epub 2021 Mar 30.

Sarah Cannon Research Institute, 1100 Martin L. King Jr. Boulevard, Nashville, TN 37203 United States.

Background: We conducted a first-in-human dose-escalation study with the oral FASN inhibitor TVB-2640 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), as monotherapy and with a taxane.

Methods: This completed open-label outpatient study was conducted at 11 sites in the United States and United Kingdom. Patients with previously-treated advanced metastatic solid tumors and adequate performance status and organ function were eligible. Read More

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Identification of an orally active carbazole aminoalcohol derivative with broad-spectrum anti-animal trypanosomiasis activity.

Acta Trop 2021 Apr 20;219:105919. Epub 2021 Apr 20.

Center for Parasitic Organisms, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, P.R. China; Ecosystems and Environment Research Centre and Biomedical Research Centre, School of Science, Engineering and Environment, University of Salford, Salford, UK. Electronic address:

Animal trypanosomiasis, caused by the members of subgenus Trypanozoon (Trypanosoma brucei brucei, T. evansi and T. equiperdum), has reduced animal productivity leading to significant negative economic impacts in endemic regions. Read More

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Design, Synthesis, Pharmacokinetics, and Biodistribution of a Series of Bone-Targeting EP4 Receptor Agonist Prodrugs for Treatment of Osteoporosis and Other Bone Conditions.

ACS Pharmacol Transl Sci 2021 Apr 10;4(2):908-925. Epub 2021 Mar 10.

Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5Z 4B4, Canada.

A series of bone-targeting EP4 receptor agonist conjugate prodrugs were prepared wherein a potent EP4 receptor agonist was bound to a biologically inactive, bisphosphonate-based bone-targeting moiety. Singly and doubly radiolabeled conjugates were synthesized and were shown to be stable in blood, to be rapidly eliminated from the bloodstream, and to be effectively taken up into bone in vivo after intravenous dosing. From these preliminary studies a preferred conjugate (also known as and Mes-1007) was selected for follow up biodistribution and elimination studies. Read More

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The insecticidal activity of recombinant nemertide toxin α-1 from Lineus longissimus towards pests and beneficial species.

Toxicon 2021 Apr 20;197:79-86. Epub 2021 Apr 20.

Durham University, Department of Biosciences, Stockton Rd, Durham, DH1 3LE, UK.

The nemertide toxins from the phylum Nemertea are a little researched family of neurotoxins with potential for development as biopesticides. Here we report the recombinant production of nemertide α-1 (α-1), a 65-residue inhibitor cystine knot (ICK) peptide from Lineus longissimus, known to target insect voltage-gated sodium channels. The insecticidal activity of α-1 was assessed and compared with the well characterised ICK venom peptide, ω-atracotoxin/hexatoxin-Hv1a (Hv1a). Read More

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