517856-55-2Relevant academic research and scientific papers
Novel vanilloid receptor-1 antagonists: 3. The identification of a second-generation clinical candidate with improved physicochemical and pharmacokinetic properties
Wang, Hui-Ling,Katon, Jodie,Balan, Chenera,Bannon, Anthony W.,Bernard, Charles,Doherty, Elizabeth M.,Dominguez, Celia,Gavva, Narender R.,Gore, Vijay,Ma, Vu,Nishimura, Nobuko,Surapaneni, Sekhar,Tang, Phi,Tamir, Rami,Thiel, Oliver,Treanor, James J. S.,Norman, Mark H.
, p. 3528 - 3539 (2008/02/09)
Based on the previously reported clinical candidate, AMG 517 (compound 1), a series of related piperazinylpyrimidine analogues were synthesized and evaluated as antagonists of the vanilloid 1 receptor (VR1 or TRPV1). Optimization of in vitro potency and physicochemical and pharmacokinetic properties led to the discovery of (R)-N-(4-(6-(4-(1-(4-fluorophenyl)ethyl) piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]-thiazol-2-yl)acetamide (16p), a potent TRPV1 antagonist [rTRPV1(CAP) IC50 = 3.7 nM] with excellent aqueous solubility (≥200 μg/mL in 0.01 N HCl) and a reduced half-life (rat t 1/2 = 3.8 h, dog t1/2 = 2.7 h, monkey t1/2 = 3.2 h) as compared to AMG 517. In addition, compound 16p was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo (ED 50 = 1.9 mg/kg, p.o. in the capsaicin-induced flinch model in rats) and was also effective at reducing thermal hyperalgesia induced by complete Freund's adjuvant in rats (MED = 1 mg/kg, p.o). Based on its improved overall profile, compound 16p (AMG 628) was selected as a second-generation candidate for further evaluation in human clinical trials as a potential new treatment for chronic pain.
