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

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journal contribution
posted on 10.02.2011, 00:00 by Victor J. Cee, Mike Frohn, Brian A. Lanman, Jennifer Golden, Kristine Muller, Susana Neira, Alex Pickrell, Heather Arnett, Janet Buys, Anu Gore, Mike Fiorino, Michelle Horner, Andrea Itano, Matt R. Lee, Michele McElvain, Scot Middleton, Michael Schrag, Dalia Rivenzon-Segal, Hugo M. Vargas, Han Xu, Yang Xu, Xuxia Zhang, Jerry Siu, Min Wong, Roland W. Bürli
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.