Jeffrey E. Merit

Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepines as novel TRPV1 antagonists

Utilization of a tetrahydro-pyrimdoazepine core as a bioisosteric replacement for a piperazine-urea resulted in the discovery a novel series of potent antagonists of TRPV1. The tetrahydro-pyrimdoazepines have been identified as having good in vitro and in vivo potency and acceptable physical properties.

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

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.