Initial structure-activity relationships of lysophosphatidic acid receptor antagonists:: discovery of a high-affinity LPA1/LPA3 receptor antagonist

被引：57

作者：

Heasley, BH

Jarosz, R

Lynch, KR

Macdonald, TL

机构：

[1] Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA

[2] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22904 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 11期

关键词：

lysophosphatidic acid; antagonist;

D O I：

10.1016/j.bmcl.2004.03.076

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A recently reported dual LPA(1)/LPA(3) 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. LPA(1)-selective (14b) and LPA(3)-selective (10g,m) compounds of modest potency have been discovered. Additionally, 2-pyridyl derivative 10t exhibits a K-i value of 18 nM at the LPA(1) receptor and is significantly more potent than 1 at the LPA(3) receptor. This paper describes the synthetic methods, biological evaluation, and structure-activity relationships (SARs) of LPA receptor antagonists. (C) 2004 Elsevier Ltd. All rights reserved.

引用

收藏

页码：2735 / 2740

页数：6

相关论文

共 14 条

[1] ENANTIOSPECIFIC AND DIASTEREOSELECTIVE SYNTHESIS OF 4,4-DISUBSTITUTED-3-AMINO-2-AZETIDINONES, STARTING FROM D-SERINE [J].

AGENO, G ;

BANFI, L ;

CASCIO, G ;

GUANTI, G ;

MANGHISI, E ;

RIVA, R ;

ROCCA, V .

TETRAHEDRON, 1995, 51 (29) :8121-8134

[2] Lysophosphatidic acid receptors [J].

Contos, JJA ;

Ishii, I ;

Chun, J .

MOLECULAR PHARMACOLOGY, 2000, 58 (06) :1188-1196

[3] Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acids [J].

Hayashi, K ;

Takahashi, M ;

Nishida, W ;

Yoshida, K ;

Ohkawa, Y ;

Kitabatake, A ;

Aoki, J ;

Arai, H ;

Sobue, K .

CIRCULATION RESEARCH, 2001, 89 (03) :251-258

[4] Activity of 2-substituted lysophosphatidic acid (LPA) analogs at LPA receptors:: Discovery of a LPA1/LPA3 receptor antagonist [J].

Heise, CE ;

Santos, WL ;

Schreihofer, AM ;

Heasley, BH ;

Mukhin, YV ;

MacDonald, TL ;

Lynch, KR .

MOLECULAR PHARMACOLOGY, 2001, 60 (06) :1173-1180

[5] Characterization of a receptor subtype-selective lysophosphatidic acid mimetic [J].

Hooks, SB ;

Ragan, SP ;

Hopper, DW ;

Honemann, CW ;

Durieux, ME ;

MacDonald, TL ;

Lynch, KR .

MOLECULAR PHARMACOLOGY, 1998, 53 (02) :188-194

[6] Molecular cloning and characterization of a lysophosphatidic acid receptor, Edg-7, expressed in prostate [J].

Im, DS ;

Heise, CE ;

Harding, MA ;

George, SR ;

O'Dowd, BF ;

Theodorescu, D ;

Lynch, KR .

MOLECULAR PHARMACOLOGY, 2000, 57 (04) :753-759

[7] Structure activity relationships of lysophospholipid mediators [J].

Lynch, KR ;

Macdonald, TL .

PROSTAGLANDINS & OTHER LIPID MEDIATORS, 2001, 64 (1-4) :33-45

[8] Identification of an intracellular receptor for lysophosphatidic acid (LPA):: LPA is a transcellular PPARγ agonist [J].

McIntyre, TM ;

Pontsler, AV ;

Silva, AR ;

St Hilaire, A ;

Xu, Y ;

Hinshaw, JC ;

Zimmerman, GA ;

Hama, K ;

Aoki, J ;

Arai, H ;

Prestwich, GD .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (01) :131-136

[9] The emerging role of lysophosphatidic acid in cancer [J].

Mills, GB ;

Moolenaar, WH .

NATURE REVIEWS CANCER, 2003, 3 (08) :582-591

[10] Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family [J].

Noguchi, K ;

Ishii, S ;

Shimizu, T .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (28) :25600-25606