Discovery of AMG 369, a Thiazolo[5,4-b]pyridine Agonist of S1P1 and S1P5

• Published in: ACS medicinal chemistry letters Vol. 2; no. 2; pp. 107 - 112
• Main Authors: Cee, Victor J, Frohn, Mike, Lanman, Brian A, Golden, Jennifer, Muller, Kristine, Neira, Susana, Pickrell, Alex, Arnett, Heather, Buys, Janet, Gore, Anu, Fiorino, Mike, Horner, Michelle, Itano, Andrea, Lee, Matt R, McElvain, Michele, Middleton, Scot, Schrag, Michael, Rivenzon-Segal, Dalia, Vargas, Hugo M, Xu, Han, Xu, Yang, Zhang, Xuxia, Siu, Jerry, Wong, Min, Bürli, Roland W
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10-02-2011
• Subjects: Letter; S1P1; Sphingosine-1-phosphate receptor; inflammation; multiple sclerosis; lymphocyte
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml100306h

The optimization of a series of thiazolopyridine S1P1 agonists with limited activity at the S1P3 receptor is reported. These efforts resulted in the discovery of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid (5d, AMG 369), a potent dual S1P1/S1P5 agonist with limited activity at S1P3 and no activity at S1P2/S1P4. Dosed orally at 0.1 mg/kg, 5d is shown to reduce blood lymphocyte counts 24 h postdose and delay the onset and reduce the severity of experimental autoimmune encephalomyelitis in rat.