Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands

Gangadhar G. Durgam, Ryoko Tsukahara, Natalia Makarova, Michelle D. Walker, Yuko Fujiwara, Kathryn R. Pigg, Daniel L. Baker, Vineet M. Sardar, Abby L. Parrill, Gabor Tigyi, Duane Miller

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Short-chain phosphatidic acid derivatives, dioctanoyl glycerol pyrophosphate (DGPP 8:0, 1) and phosphatidic acid 8:0 (PA 8:0, 2), were previously identified as subtype-selective LPA1 and LPA3 receptor antagonists. Recently, we reported that the replacement of the phosphate headgroup by thiophosphate in a series of fatty alcohol phosphates (FAP) improves agonist as well as antagonist activities at LPA GPCR. Here, we report the synthesis of stereoisomers of PA 8:0 analogs and their biological evaluation at LPA GPCR, PPARγ, and ATX. The results indicate that LPA receptors stereoselectively interact with glycerol backbone modified ligands. We observed entirely stereospecific responses by dioctyl PA 8:0 compounds, in which (R)-isomers were found to be agonists and (S)-isomers were antagonists of LPA GPCR. From this series, we identified compound 13b as the most potent LPA3 receptor subtype-selective agonist (EC50 = 3 nM), and 8b as a potent and selective LPA3 receptor antagonist (Ki = 5 nM) and inhibitor of ATX (IC50 = 600 nM). Serinediamide phosphate 19b was identified as an LPA3 receptor specific antagonist with no effect on LPA1, LPA2, and PPARγ.

Original languageEnglish (US)
Pages (from-to)633-640
Number of pages8
JournalBioorganic and Medicinal Chemistry Letters
Volume16
Issue number3
DOIs
StatePublished - Feb 1 2006

Fingerprint

Lysophosphatidic Acid Receptors
Phosphatidic Acids
Pharmacology
Ligands
Derivatives
Peroxisome Proliferator-Activated Receptors
Phosphates
Isomers
Glycerol
Fatty Alcohols
Stereoisomerism
Inhibitory Concentration 50

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands. / Durgam, Gangadhar G.; Tsukahara, Ryoko; Makarova, Natalia; Walker, Michelle D.; Fujiwara, Yuko; Pigg, Kathryn R.; Baker, Daniel L.; Sardar, Vineet M.; Parrill, Abby L.; Tigyi, Gabor; Miller, Duane.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 16, No. 3, 01.02.2006, p. 633-640.

Research output: Contribution to journalArticle

Durgam, Gangadhar G. ; Tsukahara, Ryoko ; Makarova, Natalia ; Walker, Michelle D. ; Fujiwara, Yuko ; Pigg, Kathryn R. ; Baker, Daniel L. ; Sardar, Vineet M. ; Parrill, Abby L. ; Tigyi, Gabor ; Miller, Duane. / Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands. In: Bioorganic and Medicinal Chemistry Letters. 2006 ; Vol. 16, No. 3. pp. 633-640.
@article{ae084c154d9742d6a4356fe937d77508,
title = "Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands",
abstract = "Short-chain phosphatidic acid derivatives, dioctanoyl glycerol pyrophosphate (DGPP 8:0, 1) and phosphatidic acid 8:0 (PA 8:0, 2), were previously identified as subtype-selective LPA1 and LPA3 receptor antagonists. Recently, we reported that the replacement of the phosphate headgroup by thiophosphate in a series of fatty alcohol phosphates (FAP) improves agonist as well as antagonist activities at LPA GPCR. Here, we report the synthesis of stereoisomers of PA 8:0 analogs and their biological evaluation at LPA GPCR, PPARγ, and ATX. The results indicate that LPA receptors stereoselectively interact with glycerol backbone modified ligands. We observed entirely stereospecific responses by dioctyl PA 8:0 compounds, in which (R)-isomers were found to be agonists and (S)-isomers were antagonists of LPA GPCR. From this series, we identified compound 13b as the most potent LPA3 receptor subtype-selective agonist (EC50 = 3 nM), and 8b as a potent and selective LPA3 receptor antagonist (Ki = 5 nM) and inhibitor of ATX (IC50 = 600 nM). Serinediamide phosphate 19b was identified as an LPA3 receptor specific antagonist with no effect on LPA1, LPA2, and PPARγ.",
author = "Durgam, {Gangadhar G.} and Ryoko Tsukahara and Natalia Makarova and Walker, {Michelle D.} and Yuko Fujiwara and Pigg, {Kathryn R.} and Baker, {Daniel L.} and Sardar, {Vineet M.} and Parrill, {Abby L.} and Gabor Tigyi and Duane Miller",
year = "2006",
month = "2",
day = "1",
doi = "10.1016/j.bmcl.2005.10.031",
language = "English (US)",
volume = "16",
pages = "633--640",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "3",

}

TY - JOUR

T1 - Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands

AU - Durgam, Gangadhar G.

AU - Tsukahara, Ryoko

AU - Makarova, Natalia

AU - Walker, Michelle D.

AU - Fujiwara, Yuko

AU - Pigg, Kathryn R.

AU - Baker, Daniel L.

AU - Sardar, Vineet M.

AU - Parrill, Abby L.

AU - Tigyi, Gabor

AU - Miller, Duane

PY - 2006/2/1

Y1 - 2006/2/1

N2 - Short-chain phosphatidic acid derivatives, dioctanoyl glycerol pyrophosphate (DGPP 8:0, 1) and phosphatidic acid 8:0 (PA 8:0, 2), were previously identified as subtype-selective LPA1 and LPA3 receptor antagonists. Recently, we reported that the replacement of the phosphate headgroup by thiophosphate in a series of fatty alcohol phosphates (FAP) improves agonist as well as antagonist activities at LPA GPCR. Here, we report the synthesis of stereoisomers of PA 8:0 analogs and their biological evaluation at LPA GPCR, PPARγ, and ATX. The results indicate that LPA receptors stereoselectively interact with glycerol backbone modified ligands. We observed entirely stereospecific responses by dioctyl PA 8:0 compounds, in which (R)-isomers were found to be agonists and (S)-isomers were antagonists of LPA GPCR. From this series, we identified compound 13b as the most potent LPA3 receptor subtype-selective agonist (EC50 = 3 nM), and 8b as a potent and selective LPA3 receptor antagonist (Ki = 5 nM) and inhibitor of ATX (IC50 = 600 nM). Serinediamide phosphate 19b was identified as an LPA3 receptor specific antagonist with no effect on LPA1, LPA2, and PPARγ.

AB - Short-chain phosphatidic acid derivatives, dioctanoyl glycerol pyrophosphate (DGPP 8:0, 1) and phosphatidic acid 8:0 (PA 8:0, 2), were previously identified as subtype-selective LPA1 and LPA3 receptor antagonists. Recently, we reported that the replacement of the phosphate headgroup by thiophosphate in a series of fatty alcohol phosphates (FAP) improves agonist as well as antagonist activities at LPA GPCR. Here, we report the synthesis of stereoisomers of PA 8:0 analogs and their biological evaluation at LPA GPCR, PPARγ, and ATX. The results indicate that LPA receptors stereoselectively interact with glycerol backbone modified ligands. We observed entirely stereospecific responses by dioctyl PA 8:0 compounds, in which (R)-isomers were found to be agonists and (S)-isomers were antagonists of LPA GPCR. From this series, we identified compound 13b as the most potent LPA3 receptor subtype-selective agonist (EC50 = 3 nM), and 8b as a potent and selective LPA3 receptor antagonist (Ki = 5 nM) and inhibitor of ATX (IC50 = 600 nM). Serinediamide phosphate 19b was identified as an LPA3 receptor specific antagonist with no effect on LPA1, LPA2, and PPARγ.

UR - http://www.scopus.com/inward/record.url?scp=29544431964&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=29544431964&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2005.10.031

DO - 10.1016/j.bmcl.2005.10.031

M3 - Article

VL - 16

SP - 633

EP - 640

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 3

ER -