1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines as TRPV1 antagonists with improved properties.

Abstract Based upon a previously reported lead compound 1 , a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5 H -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.