Dalia Rivenzon-Segal

Publications (3)2.65 Total impact

• Article: Novel 5- and 6-subtituted benzothiazoles with improved physicochemical properties: potent S1P₁ agonists with in vivo lymphocyte-depleting activity.

  Mike Frohn, Victor J Cee, Brian A Lanman, Alexander J Pickrell, Jennifer Golden, Dalia Rivenzon-Segal, Scot Middleton, Mike Fiorino, Han Xu, Michael Schrag, Yang Xu, Michele McElvain, Kristine Muller, Jerry Siu, Roland Bürli
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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

  Victor J. Cee, Mike Frohn, Brian A. Lanman, Jennifer Golden, Kristine Muller, Susana Neira, Alex Pickrell, Heather Arnett, Janet Buys, Anu Gore, [......], Scot Middleton, Michael Schrag, Dalia Rivenzon-Segal, Hugo M. Vargas, Han Xu, Yang Xu, Xuxia Zhang, Jerry Siu, Min Wong, Roland W. Bürli
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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 sclerosis
  12/2010;
• Article: Discovery of a Potent, S1P3-Sparing Benzothiazole Agonist of Sphingosine-1-Phosphate Receptor 1 (S1P1)

  Brian A. Lanman, Victor J. Cee, Srinivasa R. Cheruku, Mike Frohn, Jennifer Golden, Jian Lin, Mercedes Lobera, Yael Marantz, Kristine M. Muller, Susana C. Neira, [......], Andrea Itano, Michele McElvain, Scot Middleton, Michael Schrag, Hugo M. Vargas, Han Xu, Yang Xu, Xuxia Zhang, Jerry Siu, Roland W. Bürli
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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; lymphocyte
  11/2010;