659729-61-0Relevant articles and documents
Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate
Doherty, Elizabeth M.,Fotsch, Christopher,Bannon, Anthony W.,Bo, Yunxin,Chen, Ning,Dominguez, Celia,Falsey, James,Gavva, Narender R.,Katon, Jodie,Nixey, Thomas,Ognyanov, Vassil I.,Pettus, Liping,Rzasa, Robert M.,Stec, Markian,Surapaneni, Sekhar,Tamir, Rami,Zhu, Jiawang,Treanor, James J. S.,Norman, Mark H.
, p. 3515 - 3527 (2008/02/08)
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.
VANILLOID RECEPTOR LIGANDS AND THEIR USE IN TREATMENTS
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Page/Page column 28, (2008/06/13)
Pyrimidine ethers and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.
Synthesis and SAR of novel imidazoquinoxaline-based Lck inhibitors: Improvement of cell potency
Chen, Ping,Iwanowicz, Edwin J.,Norris, Derek,Gu, Henry H.,Lin, James,Moquin, Robert V.,Das, Jagabandhu,Wityak, John,Spergel, Steven H.,De Fex, Henry,Pang, Suhong,Pitt, Sydney,Shen, Ding Ren,Schieven, Gary L.,Barrish, Joel C.
, p. 3153 - 3156 (2007/10/03)
A series of anilino(imidazoquinoxaline) analogues bearing solubilizing side chains at the 6- and 7-positions of the fused phenyl ring has been prepared and evaluated for inhibition against Lck enzyme and of T-cell proliferation. Significant improvement of the cellular activity was achieved over the initial lead, compound 2.
