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

Abstract: 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 (⩾200μg/mL, 0.01 HCl; 6.7μg/mL, phosphate buffered saline (PBS); 150μg/mL, fasted-state simulated intestinal fluid (SIF)) was significantly improved over 1. In addition, compound 26 was found to be orally bioavailable (rat F oral =24%) and had potent TRPV1 antagonist activity (capsaicin IC50 =1.5nM) comparable to that of 1. [Copyright &y& Elsevier]