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

Bioorg Med Chem Lett. 2007 Dec 1;17(23):6539-45. doi: 10.1016/j.bmcl.2007.09.080.

Xianghong Wang ¹, Partha P Chakrabarti, Vassil I Ognyanov, Liping H Pettus, Rami Tamir, Helming Tan, Phi Tang, James J S Treanor, Narender R Gavva, Mark H Norman

Affiliations

Affiliation

1 Department of Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. [email protected]

PMID: 17937985 DOI: 10.1016/j.bmcl.2007.09.080

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 (>or=200microg/mL, 0.01 HCl; 6.7microg/mL, phosphate buffered saline (PBS); 150microg/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 IC(50)=1.5nM) comparable to that of 1.

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