Highly functionalized 7-azaindoles as selective PPARγ modulators

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 17; pp. 4798 - 4801
• Main Authors: Debenham, Sheryl D., Chan, Audrey, Lau, Fiona WaiYu, Liu, Weiguo, Wood, Harold B., Lemme, Karen, Colwell, Lawrence, Habulihaz, Bahanu, Akiyama, Taro E., Einstein, Monica, Doebber, Thomas W., Sharma, Neelam, Wang, Chaunlin F., Wu, Margaret, Berger, Joel P., Meinke, Peter T.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2008; Elsevier
• Subjects: Animals; Azaindole; Biological and medical sciences; General and cellular metabolism. Vitamins; Humans; Indole; Indoles - chemistry; Indoles - pharmacology; Medical sciences; Mice; Pharmacology. Drug treatments; PPAR; PPAR gamma - agonists; PPAR gamma - metabolism; Rats; Rats, Sprague-Dawley; Selective PPAR modulator; SPPARM; PPAR; Indole; Azaindole; Selective PPAR modulator; SPPARM; Nuclear receptor; PPAR;Azaindole;Indole;Selective PPAR modulator;SPPARM; Intravenous administration; Rat; Rodentia; Oral administration; Propionic acid derivatives; PPAR-γ receptor; In vitro; In vivo; Vertebrata; Mammalia; Functionalization; Structure activity relation; Mouse; Animal; Pharmacokinetics; Biological receptor
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.07.103

A series of highly functionalized 3-aroyl and 3-phenoxy-2-methyl-7-azaindoles have been identified, which are potent selective PPARγ modulators (SPPARγMs). The SAR around substitution at the 6-position of the azaindole as well as substitution of the N-benzyl moiety is reported. 7-Azaindoles have significantly improved off-target profiles compared to the parent indole series. A series of highly functionalized 3-aroyl and 3-phenoxy-2-methyl-7-azaindoles have been identified, which are potent selective PPARγ modulators (SPPARγMs). Addition of substituents at the 6-position of the 7-azaindoles improves in vitro potency and pharmacokinetics. 7-Azaindoles have significantly improved off-target profiles compared to the parent indole series.