VPC
Receptor-Selective Agonists & Antagonists

• LPA₁/LPA₃ Receptor Antagonist
• LPA Receptor Agonist
• S1P1 Antagonist
• S1P1 Control Molecule
• S1P₁/S1P₃ Receptor Antagonist
• S1P₁/S1P₃ Receptor Agonist
  

1. Heasley, B.H., R. Jarosz, K.R. Lynch, and T.L. Macdonald.
   (2004)
   Initial structure-activity relationships of lysophosphatidic acid receptor antagonists: discovery of a high-affinity LPA1/LPA3 receptor antagonist
   Bioorg Med Chem Lett 14:2735-40.
   [PubMed]
   A recently reported dual LPA1/LPA3 receptor antagonist (VPC12249, 1) has been modified herein so as to optimize potency and selectivity at LPA receptors. Compounds containing variation in the acyl lipid chain and linker region have been synthesized and screened for activity at individual LPA receptors. LPA1-selective (14b) and LPA3-selective (10g,m) compounds of modest potency have been discovered. Additionally, 2-pyridyl derivative 10t exhibits a Ki value of 18 nM at the LPA1 receptor and is significantly more potent than 1 at the LPA3 receptor. This paper describes the synthetic methods, biological evaluation, and structure-activity relationships (SARs) of LPA receptor antagonists.
   
   
2. Davis MD, Clemens JJ, Macdonald TL, Lynch KR.
   Sphingosine-1-phosphate analogs as receptor antagonists.
   J Biol Chem. 2004 Dec 8; [Epub ahead of print]
   [PubMed]
   Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that evokes a variety of cell and tissue responses via a set of cell surface receptors. The recent development of S1P receptor agonists, led by the immunomodulatory prodrug FTY720, has revealed that S1P signaling is an important regulator of lymphocyte trafficking. With the twin goals of understanding structure-activity relationships (SAR) of S1P ligands and developing tool compounds to explore S1P biology, we synthesized and tested numerous S1P analogs. We report herein that a subset of our aryl amide-containing compounds are antagonists at the S1P{sub}1 and S1P{sub}3 receptors. The lead compound in the series, VPC23019, was found in broken cell and whole cell assays to behave as a competitive antagonist at the S1P{sub}1 and S1P{sub}3 receptors. The SAR of this series is steep; for example, a slight modification of the lead compound resulted in VPC25239, which was one log order more potent at the S1P{sub}3 receptor. These new chemical entities will enable further understanding of S1P signaling and provide leads for further S1P receptor antagonist development.
   
   
3. Clemens, J.J., M.D. Davis, K.R. Lynch, and T.L. Macdonald.
   (2004)
   Synthesis of benzimidazole based analogues of sphingosine-1-phosphate: discovery of potent, subtype-selective S1P4 receptor agonists.
   Bioorg Med Chem Lett 14:4903-6.
   [PubMed]
   Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid with the capacity to induce a broad range of cellular responses via its interaction with the S1P family of G-protein coupled receptors. A member of this receptor family, S1P(4), is highly and almost exclusively expressed in the lymphoid system and has been implicated in regulation of cell shape and motility. This report describes the synthesis of several potent benzimidazole based S1P(4) receptor selective agonists. For instance, compound 9b displayed an EC(50)=36 nM at the S1P(4) receptor using a [gamma-(35)S]GTP binding assay as compared to an EC(50)=37 nM for the endogenous ligand. We also report the effects
   of altering stereochemistry at the C2 position, methylation at the C1 and C2 position, and activity differences between the alcohol and phosphate head groups of the analogues.
   
   
4. Heasley, B.H., R. Jarosz, K.M. Carter, S.J. Van, K.R. Lynch, and T.L. Macdonald.
   (2004).
   A novel series of 2-pyridyl-containing compounds as lysophosphatidic acid receptor antagonists: development of a nonhydrolyzable LPA3 receptor-selective antagonist.
   Bioorg Med Chem Lett 14:4069-74.
   [PubMed]
   A recently reported dual LPA(1)/LPA(3) receptor antagonist (1) has been modified so as to modulate the basicity, sterics, and dipole moment of the 2-pyridyl moiety. Additionally, the implications of installing nonhydrolyzable phosphate head group isosteres with regard to antagonist potency and selectivity at LPA receptors is described. This study has resulted in the development of the first nonhydrolyzable and presumably phosphatase-resistant LPA(3)-selective antagonist reported to date.
   
   
5. Santos, W.L., B.H. Heasley, R. Jarosz, K.M. Carter, K.R. Lynch, and T.L. Macdonald.
   (2004).
   Synthesis and biological evaluation of phosphonic and thiophosphoric acid derivatives of lysophosphatidic acid.
   Bioorg Med Chem Lett 14:3473-6.
   [PubMed]
   Using an N-oleoyl ethanolamide scaffold, a series of phosphate polar head group analogues of LPA comprised of various alphasubstituted phosphonates and thiophosphates was prepared. In a broken cell GTP[gamma35S] binding assay, agonist activity was evaluated at the three LPA receptors of the endothelial differentiation gene (Edg) family. This study has resulted in the discovery of a nonhydrolyzable LPA1- selective agonist (11). Additionally, thiophosphate 19 bears an isosteric phosphate mimetic that confers agonism at the LPA1 receptor but not LPA2.