Identification and synthesis of 2,7-diamino-thiazolo[5,4- d]pyrimidine derivatives as TRPV1 antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 1; pp. 40 - 46
• Main Authors: Lebsack, Alec D., Branstetter, Bryan J., Hack, Michael D., Xiao, Wei, Peterson, Matthew L., Nasser, Nadia, Maher, Michael P., Ao, Hong, Bhattacharya, Anindya, Kansagara, Mena, Scott, Brian P., Luo, Lin, Rynberg, Raymond, Rizzolio, Michele, Chaplan, Sandra R., Wickenden, Alan D., Guy Breitenbucher, J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 2009; Elsevier
• Subjects: Administration, Oral; Analgesics; Animals; Antagonists; Biological and medical sciences; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Rats; Structure-Activity Relationship; Thiazoles; Thiazolo-pyrimidine; Treatment Outcome; TRPV Cation Channels - antagonists & inhibitors; TRPV1; Antagonists; TRPV1; Thiazolo-pyrimidine; Rat; Rodentia; Oral administration; Bioavailability; In vitro; In vivo; Vertebrata; VR1 vanilloid receptor; TRPV1 vanilloid receptor; Mammalia; Analgesic; TRP ion channel; Structure activity relation; Animal; Chlorine Organic compounds; Antagonist; Fluorine Organic compounds; Pharmacokinetics; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.11.024

The identification and synthesis of 2,7-diamino-thiazolo[5,4- d]pyrimidines as TRPV1 antagonists is described. 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 highly potent TRPV1 antagonists, including 3. Compound 3 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia. 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 = 0.5 mg/kg in rats.