Isoform-selective thiazolo[5,4-b]pyridine S1P1 agonists possessing acyclic amino carboxylate head-groups.

Abstract Replacement of the azetidine carboxylate of an S1P 1 agonist development candidate, AMG 369, with a range of acyclic head-groups led to the identification of a novel, S1P 3 -sparing S1P 1 agonist, (−)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4- b ]pyridin-2-yl)phenyl)-2-methylbutanoic acid ( 8c ), which possessed good in vivo efficacy and pharmacokinetic properties. A 0.3 mg/kg oral dose of 8c produced a statistically significant reduction in blood lymphocyte counts 24 h post-dosing in female Lewis rats.