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

Research paper by Anthony B AB Reed, Brian A BA Lanman, Susana S Neira, Paul E PE Harrington, Kelvin K C KK Sham, Mike M Frohn, Alexander J AJ Pickrell, Andrew S AS Tasker, Anu A Gore, Mike M Fiorino, Andrea A Itano, Michele M McElvain, Scot S Middleton, Henry H Morrison, Han H Xu, et al.

Indexed on: 20 Jan '12Published on: 20 Jan '12Published in: Bioorganic & Medicinal Chemistry Letters


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 0.3mg/kg oral dose of 8c produced a statistically significant reduction in blood lymphocyte counts 24h post-dosing in female Lewis rats.

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