“…Some of these nonpeptide antagonists (Chart ) include Ro 47-0203 (Bosentan) ( 2 ), SB 209670 ( 3 ), PD 156707 ( 4 ), and A-127722 ( 5 ) . Other compounds from Bristol Myers Squibb, Zeneca, Roussel, Merck, Knoll, and Texas Biotechnology as well as from our own laboratories at Rhone-Poulenc Rorer , have been disclosed recently. 1 Endothelin Antagonists…”
The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ETA) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ETA receptor antagonists. In this paper, we describe how a pharmacophore model for ETA receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ETA receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)b utanoi c acid (12m). This compound exhibits low-nanomolar binding to the ETA receptor and a greater than 1000-fold selectivity over the ETB receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.
“…Some of these nonpeptide antagonists (Chart ) include Ro 47-0203 (Bosentan) ( 2 ), SB 209670 ( 3 ), PD 156707 ( 4 ), and A-127722 ( 5 ) . Other compounds from Bristol Myers Squibb, Zeneca, Roussel, Merck, Knoll, and Texas Biotechnology as well as from our own laboratories at Rhone-Poulenc Rorer , have been disclosed recently. 1 Endothelin Antagonists…”
The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ETA) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ETA receptor antagonists. In this paper, we describe how a pharmacophore model for ETA receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ETA receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)b utanoi c acid (12m). This compound exhibits low-nanomolar binding to the ETA receptor and a greater than 1000-fold selectivity over the ETB receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.
“…Scheme 2 illustrates the synthesis of (±)-1. The known benzyl-protected substrates 8 [5] and 9 [6] were selected as starting materials. The hydroarylation reaction of 8 with 9 efficiently proceeded via treatment with trifluoroacetic acid to afford dihydrocoumarin 10 in 76% yield.…”
The first synthesis of myristicyclin A, which was isolated from the Papua New Guinean plant Horsfieldia spicata, is described. The synthesis features acid-mediated hydroarylation reaction to form a dihydrocoumarin moiety, construction of the 2,8-dioxabicyclo[3.3.1]nonane skeleton under acidic conditions, and regioselective Friedel-Crafts acylation at a later stage.
“…The moderately selective lead structure 2,4-dibenzyloxybenzoic acid (IC 50 ET A = 9 µM, ET B < 20% at 30 µM) was discovered by a 3D pharmacophore search in 60,000 compounds of the Rhone Poulenc Rorer UK corporate database with the ChemDBS-3D system [80]. The moderately selective lead structure 2,4-dibenzyloxybenzoic acid (IC 50 ET A = 9 µM, ET B < 20% at 30 µM) was discovered by a 3D pharmacophore search in 60,000 compounds of the Rhone Poulenc Rorer UK corporate database with the ChemDBS-3D system [80].…”
Section: Endothelin a Receptormentioning
confidence: 99%
“…A common pharmacophore for endothelin A (ET A ) receptor ligands was derived from a cyclic pentapeptide and a triterpene ester. The moderately selective lead structure 2,4-dibenzyloxybenzoic acid (IC 50 ET A = 9 µM, ET B < 20% at 30 µM) was discovered by a 3D pharmacophore search in 60,000 compounds of the Rhone Poulenc Rorer UK corporate database with the ChemDBS-3D system [80] from a refined pharmacophore hypothesis and further chemical optimization [81,82]. Another research group generated two pharmacophore models of ET Aselective receptor antagonists from a training set of 18 ET A antagonists by using the HypoGen and HipHop options of the program Catalyst.…”
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