amg-517 has been researched along with Inflammation* in 2 studies
2 other study(ies) available for amg-517 and Inflammation
Article | Year |
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Discovery of novel 6,6-heterocycles as transient receptor potential vanilloid (TRPV1) antagonists.
The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration. Topics: Analgesics; Animals; Biological Availability; Capsaicin; Chlorocebus aethiops; COS Cells; Hot Temperature; Humans; Hyperalgesia; In Vitro Techniques; Inflammation; Microsomes, Liver; Naphthyridines; Pain; Pyrazines; Pyridines; Pyrimidines; Quinazolines; Quinolines; Rats; Structure-Activity Relationship; TRPV Cation Channels | 2010 |
Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate.
A series of novel 4-oxopyrimidine TRPV1 antagonists was evaluated in assays measuring the blockade of capsaicin or acid-induced influx of calcium into CHO cells expressing TRPV1. The investigation of the structure-activity relationships in the heterocyclic A-region revealed the optimum pharmacophoric elements required for activity in this series and resulted in the identification of subnanomolar TRPV1 antagonists. The most potent of these antagonists were thoroughly profiled in pharmacokinetic assays. Optimization of the heterocyclic A-region led to the design and synthesis of 23, a compound that potently blocked multiple modes of TRPV1 activation. Compound 23 was shown to be effective in a rodent "on-target" biochemical challenge model (capsaicin-induced flinch, ED50 = 0.33 mg/kg p.o.) and was antihyperalgesic in a model of inflammatory pain (CFA-induced thermal hyperalgesia, MED = 0.83 mg/kg, p.o.). Based on its in vivo efficacy and pharmacokinetic profile, compound 23 (N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide; AMG 517) was selected for further evaluation in human clinical trials. Topics: Analgesics; Animals; Benzothiazoles; Calcium; CHO Cells; Cricetinae; Cricetulus; Dogs; Drug Stability; Haplorhini; Humans; Hyperalgesia; In Vitro Techniques; Inflammation; Male; Microsomes, Liver; Pain Measurement; Pyrimidines; Rats; Rats, Sprague-Dawley; Solubility; Structure-Activity Relationship; TRPV Cation Channels | 2007 |