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.

A series of trisubstituted pyrimidines were synthesized to improve aqueous solubility of our first TRPV1 clinical candidate 1. The structure–activity and structure–solubility studies led to the discovery of 26.Figure optionsDownload as PowerPoint slide