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. Epub 2007 Oct 15.

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacology
  • CHO Cells
  • Capsaicin / antagonists & inhibitors
  • Cricetinae
  • Cricetulus
  • Drug Evaluation, Preclinical
  • Hydrogen-Ion Concentration
  • Piperazines / chemical synthesis
  • Piperazines / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Solubility / drug effects
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / biosynthesis
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / physiology

Substances

  • Benzothiazoles
  • N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide
  • Piperazines
  • Pyrimidines
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • Capsaicin