All products of the dirhodium tetraacetate catalyzed reactions of ethyl diazoacetate with furan, 2-methylfuran, 2,5-dimethylfuran, 2-ra-octylfuran, methyl furcate and methyl /3-(«-furyl)acrylate were isolated and characterized. They consist mostly of exo-cyclopropanecarboxylates and 1,4-diacyl-1,3-butadienes and some 3-(acylmethyl)furans. Treatment of the crude reaction mixtures with iodine or boron trifluoride furnishes 1,4-diacyl-1 (E) ,3 (E)-butadienes. Horner-Emmons condensation with the latter dicarbonyl compounds leads to l,6-diacyl-l,3,5-hexatrienes. Proper combinations of methyl -diazopropionate, furans, and -phosphono esters afford segments of retinol and /3-carotene, while combinations of -diazo ketones, furans, and «-phosphono ketones yield LTB3-like leukotrienes. Finally, dirhodium tetraacetate promoted decomposition of ethyl diazoacetate in l,2-bis(2-furyl)ethane and iodine treatment gives a diketo diester, whose reduction, dehydration, and hydrolysis leads to the naturally occurring dodecahexaenic dicarboxylic acid, corticrocin.
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.
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