title: Synthesis and biological evaluation of 5-substituted and 4,5-disubstituted-2-arylamino oxazole TRPV1 antagonists.
abstract: The synthesis and structure-activity relationships of a series of 5-monosubstituted and 4,5-disubstituted 2-arylaminooxazoles as novel antagonists of the transient receptor potential vanilloid 1 (TRPV1) receptor are described. The 7-hydroxy group of the tetrahydronaphthyl moiety on the 2-amino substituent of the oxazole ring was important for obtaining excellent in vitro potency at the human TRPV1 receptor, while a variety of alkyl and phenyl substituents at the 4- and 5-positions of the oxazole ring were well tolerated and yielded potent TRPV1 antagonists. Despite excellent in vitro potency, the 5-monosubstituted compounds suffered from poor pharmacokinetics. It was found that 4,5-disubstitution on the oxazole ring was critical to the improvement of the overall pharmacokinetic profile of these analogues, which led to the discovery of compound (R)-27, a novel TRPV1 antagonist with good oral activity in preclinical animal models of pain.
authors.affiliation: Neuroscience and Pain Research, Global Pharmaceutical Research and Development, Dept. R4DE AP9A/L-15, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6115, USA. richard.j.perner@abbott.com
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Perner
authors.forename: John R
authors.initials: JR
authors.lastname: Koenig
authors.forename: Stanley
authors.initials: S
authors.lastname: Didomenico
authors.forename: Arthur
authors.initials: A
authors.lastname: Gomtsyan
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schmidt
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Hsu
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Donna M
authors.initials: DM
authors.lastname: Gauvin
authors.forename: Shailen
authors.initials: S
authors.lastname: Joshi
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Turner
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D008968:Molecular Conformation; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C559341:(5-(3-methyl-4-(trifluoromethyl)phenyl)oxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol; D009284:Naphthols; D010080:Oxazoles; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human