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

• Published in: Bioorganic & medicinal chemistry 2007-12, Vol.17 (23), p.6539-6545
• Main Authors: Wang, Xianghong, Chakrabarti, Partha P., Ognyanov, Vassil I., Pettus, Liping H., Tamir, Rami, Tan, Helming, Tang, Phi, Treanor, James J.S., Gavva, Narender R., Norman, Mark H.
• Format: Article
• Language: English
• Subjects: Analgesics; Animals; Antagonists; Aqueous solubility; Benzothiazoles - chemistry; Benzothiazoles - pharmacology; Biological and medical sciences; Capsaicin - antagonists & inhibitors; CHO Cells; Cricetinae; Cricetulus; Drug Evaluation, Preclinical; Hydrogen-Ion Concentration; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Rats, Sprague-Dawley; Solubility - drug effects; Structure-Activity Relationship; Trisubstituted pyrimidines; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - biosynthesis; TRPV Cation Channels - genetics; TRPV Cation Channels - physiology; Vanilloid receptor-1
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.09.080

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. 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 F oral = 24%) and had potent TRPV1 antagonist activity (capsaicin IC 50 = 1.5 nM) comparable to that of 1.