title: 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 (>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.
authors.affiliation: Department of Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. qwang@amgen.com
authors.forename: Xianghong
authors.initials: X
authors.lastname: Wang
authors.forename: Partha P
authors.initials: PP
authors.lastname: Chakrabarti
authors.forename: Vassil I
authors.initials: VI
authors.lastname: Ognyanov
authors.forename: Liping H
authors.initials: LH
authors.lastname: Pettus
authors.forename: Rami
authors.initials: R
authors.lastname: Tamir
authors.forename: Helming
authors.initials: H
authors.lastname: Tan
authors.forename: Phi
authors.initials: P
authors.lastname: Tang
authors.forename: James J S
authors.initials: JJ
authors.lastname: Treanor
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002211:Capsaicin / Q000037:antagonists & inhibitors; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D006863:Hydrogen-Ion Concentration; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility / Q000187:drug effects; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
chemical_list: D052160:Benzothiazoles; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D010879:Piperazines; D011743:Pyrimidines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D002211:Capsaicin