SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist.

Abstract

An extremely potent and highly specific nonpeptide, subnanomolar endothelin (ET) receptor antagnist, SB 209670, has been synthesized and characterized. SB 209670, which was rationally designed using conformational models of ET-1, selectively inhibits binding of 12SI-labeled ET- Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor peptide (1). ET-1 has pronounced effects on the cardiovascular system and, in particular, on the coronary, renal, and cerebral circulatory beds. Elevated or abnormal biosynthesis/release of ET-1 may therefore be a factor in the pathogenesis of certain diseases. Two ET receptor subtypes, designated ETA and ETB, have been cloned and sequenced (2, 3). The ETA receptor is characterized by marked selectivity for ET-1 over the isopeptides ET-3 and sarafotoxin 6c (S6c), a snake venom toxin. The primary effects mediated by the ETA receptor include vasoconstriction and vascular smooth muscle cell proliferation (4-7). In contrast, the ETB receptor is characterized as exhibiting equivalent affinity toward ET-1, and S6c (3,8) and mediates the release of nitric oxide (9, 10), vasoconstriction ofcertain vascular beds, and bronchoconstriction (11-13).Exogenous administration of ET produces pronounced, long-lasting vasoconstriction and smooth muscle cell proliferation in vitro and in vivo (1, 12-16), but evidence implicating ET as an endogenous mediator of these biological phenomena is still limited and largely indirect. The development of potent and selective ET receptor antagonists will facilitate definition of the role of ET in pathological conditions. This report describes the characterization of SB 209670, which was rationally designed using conformational models of the natural ligand and, to our knowledge, is the most potent (subnanomolar) nonpeptide ET receptor antagonist identified to date.Screening 8052The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Hepatoprotective effect of the endothelin receptor antagonist TAK-044 against ischemia-reperfusion injury in the canine liver

“…Nonselective receptor antagonists such as SB209670 22 kg. This is because the reduction of the infarcted area of 15.…”

Comparison of the structures of the endothelin A receptor antagonists BQ123 andN‐methyl leucine BQ123 with the crystal structure of the C‐terminal tail of endothelin‐1

“…SAR studies on peptide and non-peptide small molecule antagonists have pointed to the importance of a juxtaposition of an acidic group (presumably Asp 18 in the native endothelin) and at least one aromatic group (in native ET this would likely be Trp 21 ). Thus, it was postulated that these types of side chains should be in 382 similar relative positions in both the small molecule and in the native peptide [34]. In BQ123 the corresponding groups would appear to be o-Asp The overlay studies reported here would suggest that the endothelin A receptor binding site has a geometry that would accommodate the tryptophan side chain as well as a closely juxtaposed carboxylate from the aspartic acid sidechain, but that the residues on the opposite side of the molecule (i.e.…”

Molecular Pharmacology and Pathophysiological Significance of Endothelin

“…Of particular interest in this connection, SB209670 strongly attenuated neointima formation following rat carotid artery balloon angioplasty (127,233). In angioplasty-induced neointima in rats, expressions of the mRNAs of endothelin-1, endothelin-3, ECE-1, ETA and ETB receptor were found to be increased (234).…”

“…Although the effects of peptide antagonists for endothelin receptors in spontaneously hypertensive rats (SHR) are currently controversial (147)(148)(149), the nonpeptide antagonist SB209670 has recently been shown to exert significant and long-lasting hypotensive actions following intraduodenal administration in this particular model of hypertension (127). The nonpeptide antagonists have been demonstrated to be effective in lowering blood pressure in various animal models of hypertension; e.g., sodium-depletion-induced hypertension in squirrel monkeys (124), renal hypertension in dogs (150) and mouse renin transgenic ((mRen-2) 27) hypertensive rats (151).…”

“…Three-dimensional peptidomimetic simulation has been further continued. As a result, an extremely potent and highly specific nonpeptide endothelin receptor antagonist, SB 209670 (SmithKline Beecham), has been synthesized and characterized (127 …”