Selecting against S1P3 enhances the acute cardiovascular tolerability of 3-(N-benzyl)aminopropylphosphonic acid S1P receptor agonists

Jeffrey J Hale; George Doherty; Leslie Toth; Sander G Mills; Richard Hajdu; Carol Ann Keohane; Mark Rosenbach; James Milligan; Gan-Ju Shei; Gary Chrebet; James Bergstrom; Deborah Card; Michael Forrest; Shu-Yu Sun; Sarah West; Huijuan Xie; Naomi Nomura; Hugh Rosen; Suzanne Mandala

doi:10.1016/j.bmcl.2004.04.070

Selecting against S1P3 enhances the acute cardiovascular tolerability of 3-(N-benzyl)aminopropylphosphonic acid S1P receptor agonists

Bioorg Med Chem Lett. 2004 Jul 5;14(13):3501-5. doi: 10.1016/j.bmcl.2004.04.070.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. [email protected]

PMID: 15177461
DOI: 10.1016/j.bmcl.2004.04.070

Abstract

Structurally modified 3-(N-benzylamino)propylphosphonic acid S1P receptor agonists that maintain affinity for S1P1, and have decreased affinity for S1P3 are efficacious, but exhibit decreased acute cardiovascular toxicity in rodents than do nonselective agonists.

MeSH terms

Animals
Benzyl Compounds / chemistry
Benzyl Compounds / pharmacology*
Binding Sites
CHO Cells
Cardiovascular System / drug effects*
Cricetinae
Humans
Inhibitory Concentration 50
Kinetics
Lysophospholipids / chemistry
Lysophospholipids / pharmacology
Mice
Myocardium / metabolism*
Organophosphorus Compounds / chemistry
Organophosphorus Compounds / pharmacology*
Phosphorus Radioisotopes
Rats
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / metabolism
Receptors, Lysosphingolipid / agonists*
Receptors, Lysosphingolipid / antagonists & inhibitors*
Sphingosine / analogs & derivatives
Sphingosine / chemistry
Sphingosine / pharmacology

Substances

3-(N-benzyl)aminopropylphosphonic acid
Benzyl Compounds
Lysophospholipids
Organophosphorus Compounds
Phosphorus Radioisotopes
Receptors, G-Protein-Coupled
Receptors, Lysosphingolipid
Sphingosine