Potent angiotensin II antagonists with non-.beta.-branched amino acids in position 5

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Abstract
Amino acids with lipophilic side chains that contain more than one functional group on the .beta.-carbon, ie.e. a .beta.-branched hydrocarbon moiety, are required in position of 5 of angiotensin II (AII) analogue with potent agonist activity. This requirement for agonist activity does not follow for AII analogues with potent antagonist activity. Straight-chain amino acids may be substituted into position 5 of [Sar1, X5, IIe8]AII with retention or enhancement of antagonist activity e.g. (X5, pA2 rabbit aorta) Phe, 9.15; Tyr, 9.6; His, 9.0; Arg, 9.0; Glu, 9.0; Nle, 8.85, compared to Ile, 9.1. .beta.-Branched side chains can still enhance the antagonist activities of [Sar1,X5,Ile8]AII analogues, e.g. X5 = (.beta.Me)Phe, pA2 = 9.3. An X-ray crystal structure of the Boc-(.beta.Me)Phe DCHA salt, prepared for the synthesis of [Sar1,-(.beta.Me)Phe5,Ile8]AII, revealed an S,S configuration of .alpha.- and .beta.-carbon atoms. Contrary to previous literature reports, chemical nonequivalence of the .delta. protons of Pro was observed in the 1H NMR spectra of [Sar1, X5, Ile8]AII analogues bearing both .beta.-branched X5 side chains (X5 = Ile) and non-.beta.-branched X5 side chains (X5 = Ala, His).