Identification and synthesis of 2,7-diamino-thiazolo[5,4-d]pyrimidine derivatives as TRPV1 antagonists.
We have identified and synthesized a series of 2,7-diamino-thiazolo[5,4-d]pyrimidines as TRPV1 antagonists. An exploration of the structure-activity relationships at the 2-, 5-, and 7-positions of the thiazolo[5,4-d]pyrimidine led to the identification of several potent TRPV1 antagonists, including 3, 29, 51, and 57. Compound 3 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia with an ED(50)=0.5mg/kg in rats.
Lebsack
Alec D
AD
Johnson & Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121, USA. alebsack@its.jnj.com
Branstetter
Bryan J
BJ
Hack
Michael D
MD
Xiao
Wei
W
Peterson
Matthew L
ML
Nasser
Nadia
N
Maher
Michael P
MP
Ao
Hong
H
Bhattacharya
Anindya
A
Kansagara
Mena
M
Scott
Brian P
BP
Luo
Lin
L
Rynberg
Raymond
R
Rizzolio
Michele
M
Chaplan
Sandra R
SR
Wickenden
Alan D
AD
Guy Breitenbucher
J
J
D000284:Administration, Oral; D000818:Animals; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D013844:Thiazoles; D016896:Treatment Outcome
D011743:Pyrimidines; D050916:TRPV Cation Channels; D013844:Thiazoles; C493922:Trpv1 protein, rat