Publications (3)2.65 Total impact
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Article: Novel 5- and 6-subtituted benzothiazoles with improved physicochemical properties: potent S1P₁ agonists with in vivo lymphocyte-depleting activity.
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ABSTRACT: An SAR campaign designed to increase polarity in the 'tail' region of benzothiazole 1 resulted in two series of structurally novel 5-and 6-substituted S1P(1) agonists. Structural optimization for potency ultimately delivered carboxamide (+)-11f, which in addition to possessing improved physicochemical properties relative to starting benzothiazole 1, also displayed good S1P(3) selectivity and acceptable in vivo lymphocyte-depleting activity.Bioorganic & medicinal chemistry letters 10/2011; 22(1):628-33. · 2.65 Impact Factor -
Article: Discovery of AMG 369, a Thiazolo[5,4-b]pyridine Agonist of S1P1 and S1P5
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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. Keywords (keywords): Sphingosine-1-phosphate receptor; S1P1; lymphocyte; inflammation; multiple sclerosis12/2010; -
Article: Discovery of a Potent, S1P3-Sparing Benzothiazole Agonist of Sphingosine-1-Phosphate Receptor 1 (S1P1)
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ABSTRACT: Optimization of a benzofuranyl S1P1 agonist lead compound (3) led to the discovery of 1-(3-fluoro-4-(5-(2-fluorobenzyl)benzo[d]thiazol-2-yl)benzyl)azetidine-3-carboxylic acid (14), a potent S1P1 agonist with minimal activity at S1P3. Dosed orally at 0.3 mg/kg, 14 significantly reduced blood lymphocyte counts 24 h postdose and attenuated a delayed type hypersensitivity (DTH) response to antigen challenge. Keywords (keywords): Sphingosine-1-phosphate receptor; S1P1; agonist; inflammation; lymphocyte11/2010;