2-Aryl(pyrrolidin-4-yl)acetic acids are potent agonists of sphingosine-1-phosphate (S1P) receptors

Lin Yan; Richard Budhu; Pei Huo; Christopher L Lynch; Jeffrey J Hale; Sander G Mills; Richard Hajdu; Carol A Keohane; Mark J Rosenbach; James A Milligan; Gan-Ju Shei; Gary Chrebet; James Bergstrom; Deborah Card; Suzanne M Mandala

doi:10.1016/j.bmcl.2006.03.090

2-Aryl(pyrrolidin-4-yl)acetic acids are potent agonists of sphingosine-1-phosphate (S1P) receptors

Bioorg Med Chem Lett. 2006 Jul 1;16(13):3564-8. doi: 10.1016/j.bmcl.2006.03.090. Epub 2006 Apr 18.

Authors

Lin Yan¹, Richard Budhu, Pei Huo, Christopher L Lynch, Jeffrey J Hale, Sander G Mills, Richard Hajdu, Carol A Keohane, Mark J Rosenbach, James A Milligan, Gan-Ju Shei, Gary Chrebet, James Bergstrom, Deborah Card, Suzanne M Mandala

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. lin_yan@merck.com

PMID: 16621543
DOI: 10.1016/j.bmcl.2006.03.090

Abstract

A series of 2-aryl(pyrrolidin-4-yl)acetic acids were synthesized and their biological activities were evaluated as agonists of S1P receptors. These analogs were able to induce lowering of lymphocyte counts in the peripheral blood of mice and were found to have good overall pharmacokinetic properties in rat.

MeSH terms

Acetates / chemical synthesis
Acetates / chemistry
Acetates / pharmacology*
Animals
Lymphocyte Count
Lysophospholipids / antagonists & inhibitors
Mice
Molecular Structure
Protein Binding / drug effects
Pyrrolidines / chemical synthesis
Pyrrolidines / chemistry
Pyrrolidines / pharmacology*
Rats
Receptors, Lysosphingolipid / agonists*
Sphingosine / analogs & derivatives
Sphingosine / antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship

Substances

Acetates
Lysophospholipids
Pyrrolidines
Receptors, Lysosphingolipid
sphingosine 1-phosphate
Sphingosine