Synthesis and biological evaluation of 5-substituted and 4,5-disubstituted-2-arylamino oxazole TRPV1 antagonists.
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.
Perner
Richard J
RJ
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
Koenig
John R
JR
Didomenico
Stanley
S
Gomtsyan
Arthur
A
Schmidt
Robert G
RG
Lee
Chih-Hung
CH
Hsu
Margaret C
MC
McDonald
Heath A
HA
Gauvin
Donna M
DM
Joshi
Shailen
S
Turner
Teresa M
TM
Reilly
Regina M
RM
Kym
Philip R
PR
Kort
Michael E
ME
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
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