1260242-68-9Relevant articles and documents
1,2-Diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d] azepines as TRPV1 antagonists with improved properties
Lebsack, Alec D.,Rech, Jason C.,Branstetter, Bryan J.,Hawryluk, Natalie A.,Merit, Jeffrey E.,Allison, Brett,Rynberg, Raymond,Buma, Johnathan,Rizzolio, Michele,Swanson, Nadia,Ao, Hong,Maher, Michael P.,Herrmann, Michelle,Freedman, Jamie,Scott, Brian P.,Luo, Lin,Bhattacharya, Anindya,Wang, Qi,Chaplan, Sandra R.,Wickenden, Alan D.,Breitenbucher, J. Guy
scheme or table, p. 7142 - 7146 (2011/01/03)
Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Structure-activity relationship studies directed toward improving the aqueous solubility (pH 2 and fasted-state simulated intestinal fluid (SIF)) and rat pharmacokinetics led to the discovery of compound 13. Aqueous solubility of compound 13 (pH 2 = >237 μg/mL and SIF = 11 μg/mL) was significantly improved over compound 1 (pH 2 = 5 μg/mL and SIF = 0.5 μg/mL). In addition, compound 13 afforded improved rat pharmacokinetics (CL = 0.7 L/kg/h) compared to compound 1 (CL = 3.1 L/kg/h). Compound 13 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia at 5 and 30 mg/kg in rats.
