The relative contributions to pressor activity of lipophilic and aromatic character for the Ph ring of position 8 phenylalanine in [Asn¹,Ile⁵]angiotensin II was evaluated by replacing the benzyl side chain with a variety of normal or branched aliphatic and substituted aromatic residues.A conformationally constrained analog in which the 2-aminoindane-2-carboxylic acid (Ind) [27473-62-7] replaced the phenylalanine residue was prepared to exam. the steric requirement for the aromatic ring for pressor activity.The analogs were synthesized by the solid-phase method and had the following pressor activities in the rat: aminoheptanoic acid⁸ [60318-02-7], 11.5%; Nle⁸ [60318-01-6], 7.3%; Leu⁸ [38027-94-0], 1.2%; Ind⁸ [71066-04-1], 0.1%; Phe(4-NH₂)⁸ [71066-07-4], 52.5%; Phe(4-NO₂)₈ [71066-05-2], 15%; and the disubstituted analogs [Sar¹,Ile⁵,Leu⁸]angiotensin II [38027-93-9], 2.5%; [des-Asp¹,D-Ala²,Ile⁵,Leu⁸]angiotensin II [71066-03-0], 1.4%; [Asn,[Tyr(3-Bzl)⁴,Ile⁵,Phe(4-NO₂)⁸]angiotensin II [70-47-3], 0.2%.In the absence of aromatic character, higher lipophilicity of the analogs resulted in higher pressor activity.However, aromaticity was more important than lipophilic character and was necessary for full activity.Steric interference, caused by a bulky substituent on the ring or by branching of the aliphatic residue, resulted in reduced potency.When the sizes of the substituents were comparable, the aromatic, π-electron-enriched analogs were more active than the π-electron-deficient analogs.The spatial orientation of the ring relative to the peptide backbone was critical for the pressor effect.The Ind⁸ analog was essentially lacking in pressor activity and was more potent than the Leu⁸ analog as an angiotensin II antagonist, in spite of its aromatic nature.The Sar¹,Leu⁸ analog was more potent and longer acting than Ind⁸ analog as an angiotensin II inhibitor.Apparently incorporation of a conformationally constrained aromatic ring in position 8 of angiotensin analogs can be an effective approach to the development of potent inhibitors with low pressor activity.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Diseases	Preclinical	India	Indus Biotech Ltd.	-

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