Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists

被引：11

作者：

Evindar, Ghotas ^{[1
]}

Bernier, Sylvie G. ^{[2
]}

Doyle, Elisabeth ^{[2
]}

Kavarana, Malcolm J. ^{[1
]}

Satz, Alexander L. ^{[1
]}

Lorusso, Jeanine ^{[2
]}

Blanchette, Heather S. ^{[2
]}

Saha, Ashis K. ^{[1
]}

Hannig, Gerhard ^{[2
]}

Morgan, Barry A. ^{[1
]}

Westlin, William F. ^{[2
]}

机构：

[1] Praecis Pharmaceut Inc, Dept Med Chem, Waltham, MA 02451 USA

[2] Praecis Pharmaceut Inc, Dept Preclin Res, Waltham, MA 02451 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 08期

关键词：

Sphingosine-1-phosphate (S1P) agonist; S1P(1) agonists; Phenylamide; Phenylimidazole; Immunosuppressants; Lymphopenia; ANALOGS; FTY720;

D O I：

10.1016/j.bmcl.2010.02.098

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

In pursuit of a potent and highly selective sphingosine-1-phosphate receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2520 / 2524

页数：5

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