STRUCTURE-ACTIVITY-RELATIONSHIPS OF THE POTENT COMBINED ENDOTHELIN-A ENDOTHELIN-B RECEPTOR ANTAGONIST AC-DDIP(16)-LEU-ASP-ILE-ILE-TRP(21) - DEVELOPMENT OF ENDOTHELIN-B RECEPTOR-SELECTIVE ANTAGONISTS

被引：31

作者：

CODY, WL ^{[1
]}

HE, JX ^{[1
]}

DEPUE, PL ^{[1
]}

WAITE, LA ^{[1
]}

LEONARD, DM ^{[1
]}

SEFLER, AM ^{[1
]}

KALTENBRONN, JS ^{[1
]}

HALEEN, SJ ^{[1
]}

WALKER, DM ^{[1
]}

FLYNN, MA ^{[1
]}

WELCH, KM ^{[1
]}

REYNOLDS, EE ^{[1
]}

DOHERTY, AM ^{[1
]}

机构：

[1] WARNER LAMBERT PARKE DAVIS,PARKE DAVIS PHARMACEUT RES,DEPT CARDIOVASC THERAPEUT,ANN ARBOR,MI 48105

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1995年 / 38卷 / 15期

关键词：

D O I：

10.1021/jm00015a003

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The endothelins (ETs) are a family of bicyclic 21-amino acid-containing peptides that are highly potent and prolonged vasoconstrictors. The discovery of potent ET antagonists will facilitate the understanding of the physiological and/or pathophysiological role of ET. Structure-activity studies have revealed the importance of the C-terminal hexapeptide (residues 16-21) of ET (His(16)-Leu(17)-Asp(18)-Ile(19)-Ile(20)-Trp(21)) to the development of Potent antagonists at both receptor subtypes (ET(A) and ET(B)). In particular, it has been shown that Ac-DDip(16)-Leu-Asp-Ile-Ile-Trp(21) (Dip = 3,3-diphenylalanine) has low nanomolar affinity for the two endothelin receptor subtypes and is a functional antagonist of ET activity, both in vitro and in vivo at both receptors. Herein, we will describe the structure-activity relationships of Ac-DDip(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 142893) with a particular emphasis on modifications that lead to enhanced receptor affinity and/or individual receptor subtype selectivity. In particular, we will demonstrate how we utilized PD 142893 to develop ET(B) receptor selective ligands and the pharmacological differences that exist between species ET(B) receptors with respect to their affinity for C-terminal hexapeptide antagonists.

引用

页码：2809 / 2819

页数：11

共 68 条

[1] CLONING AND EXPRESSION OF A CDNA-ENCODING AN ENDOTHELIN RECEPTOR [J].