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

ABSTRACT: 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.

SUBMITTER: Cee VJ

PROVIDER: S-EPMC4018127 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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

Cee Victor J VJ Frohn Mike M Lanman Brian A BA Golden Jennifer J Muller Kristine K Neira Susana S Pickrell Alex A Arnett Heather H Buys Janet J Gore Anu A Fiorino Mike M Horner Michelle M Itano Andrea A Lee Matt R MR McElvain Michele M Middleton Scot S Schrag Michael M Rivenzon-Segal Dalia D Vargas Hugo M HM Xu Han H Xu Yang Y Zhang Xuxia X Siu Jerry J Wong Min M Bürli Roland W RW

ACS medicinal chemistry letters 20101229 2

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 severit ...[more]

PMID: 24900288

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