Trisubstituted pyrimidines as transient receptor potential vanilloid 1 (TRPV1) antagonists with improved solubility

A series of trisubstituted pyrimidines were synthesized to improve aqueous solubility of our first TRPV1 clinical candidate (1; AMG 517), while maintaining potent TRPV1 inhibitory activity. Structure–activity and structure–solubility studies led to the identification of compound 26. The aqueous solubility of 26 ( 200 μg/mL, 0.01 HCl; 6.7 μg/mL, phosphate buffered saline (PBS); 150 μg/mL, fasted-state simulated intestinal fluid (SIF)) was significantly improved over 1. In addition, compound 26 was found to be orally bioavailable (rat Foral = 24%) and had potent TRPV1 antagonist activity (capsaicin IC50 = 1.5 nM) comparable to that of 1.