title: Identification and synthesis of 2,7-diamino-thiazolo[5,4-d]pyrimidine derivatives as TRPV1 antagonists.
abstract: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121, USA. alebsack@its.jnj.com
authors.forename: Alec D
authors.initials: AD
authors.lastname: Lebsack
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Branstetter
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hack
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Peterson
authors.forename: Nadia
authors.initials: N
authors.lastname: Nasser
authors.forename: Michael P
authors.initials: MP
authors.lastname: Maher
authors.forename: Hong
authors.initials: H
authors.lastname: Ao
authors.forename: Anindya
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Mena
authors.initials: M
authors.lastname: Kansagara
authors.forename: Brian P
authors.initials: BP
authors.lastname: Scott
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.forename: Raymond
authors.initials: R
authors.lastname: Rynberg
authors.forename: Michele
authors.initials: M
authors.lastname: Rizzolio
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Chaplan
authors.forename: Alan D
authors.initials: AD
authors.lastname: Wickenden
authors.forename: J
authors.initials: J
authors.lastname: Guy Breitenbucher
mesh_terms: 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
chemical_list: D011743:Pyrimidines; D050916:TRPV Cation Channels; D013844:Thiazoles; C493922:Trpv1 protein, rat