Angiotensin converting enzyme inhibitors: 1-glutarylindoline-2-carboxylic acids derivatives.
01 Sep 1983-Journal of Medicinal Chemistry (American Chemical Society)-Vol. 26, Iss: 9, pp 1277-1282
TL;DR: The preparation of a series of 1-glutarylindoline-2(S)-carboxylic acid derivatives, 6a-v and 21a-c, is described and the structure-activity relationship of the series is discussed.
Abstract: The preparation of a series of 1-glutarylindoline-2(S)-carboxylic acid derivatives, 6a-v and 21a-c, is described The above compounds were tested for inhibition of angiotensin converting enzyme The structure-activity relationship of the series is also discussed Compound 6u, the most potent member of the series, had an in vitro IC50 of 48 X 10(-9) M Compound 6v, an ethyl ester of 6u, lowered blood pressure 70 mm in spontaneous hypertensive rats at an oral dose of 30 mg/kg
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TL;DR: The potential synthetic utility of the present method for the practical asymmetric synthesis of structurally diverse natural and unnatural alpha-amino acids has been demonstrated by its successful application to the facile asymmetric syntheses of (S)-N-acetylindoline-2-carboxylate, a key intermediate in the synthesis of the ACE inhibitor, and l-Dopa (l-3,4-dihydroxyphenylalanine) ester and its analogue.
Abstract: A series of C2-symmetric chiral quaternary ammonium bromides 10 and 11 have been designed as a new, purely synthetic chiral phase-transfer catalyst, and readily prepared from commercially available optically pure 1,1‘-bi-2-naphthol as a basic chiral unit. The details of the synthetic procedures of each requisite chiral binaphthyl subunit have been disclosed, and the structures of the assembled N-spiro chiral quaternary ammonium bromides 11a and 11f were unequivocally determined by single-crystal X-ray diffraction analysis. The reactivity and selectivity of these chiral ammonium bromides as chiral phase-transfer catalysts have been evaluated in the asymmetric alkylation of the benzophenone Schiff base of glycine ester 7 under mild liquid−liquid phase-transfer conditions, and the optimization of the reaction variables (solvent, base, and temperature) has also been conducted. Further, the scope and limitations of this asymmetric alkylation have been thoroughly investigated with a variety of alkyl halides, in...
296 citations
TL;DR: It is hoped that some of the insights to be derived from the SAR and structural studies done with ACE inhibitors will be applicable to other enzyme targets as well.
Abstract: Orally-active angiotensin-converting enzyme inhibitors are rapidly establishing themselves in the therapy of hypertension and congestive heart failure. Concerted efforts in a number of laboratories have now led to the discovery or synthesis of an unparalleled variety of potent inhibitors. The manner in which several of these inhibitors bind to ACE is beginning to be understood. It is hoped that some of the insights to be derived from the SAR and structural studies done with ACE inhibitors will be applicable to other enzyme targets as well. The success of ACE inhibitors as pharmacological tools and in the clinic will also quite certainly encourage future efforts to develop new enzyme inhibitor approaches to drug therapy.
246 citations
TL;DR: By placing the carboxyl binding group, the binding site for amido carbonyl, and the Zn atom site in positions determined by ideal binding geometry with the inhibitors' functional groups, it was possible to clearly specify a geometry for the active site of ACE.
Abstract: Previous structure-activity studies of captopril and related active angiotensin-converting enzyme (ACE) inhibitors have led to the conclusion that the basic structural requirements for inhibition of ACE involve (a) a terminal carboxyl group; (b) an amido carbonyl group; and (c) different types of effective zinc (Zn) ligand functional groups. Such structural requirements common to a set of compounds acting at the same receptor have been used to define a pharmacophoric pattern of atoms or groups of atoms mutually oriented in space that is necessary for ACE inhibition from a stereochemical point of view. A unique pharmacophore model (within the resolution of approximately 0.15 A) was observed using a method for systematic search of the conformational hyperspace available to the 28 structurally different molecules under study. The method does not assume a common molecular framework, and, therefore, allows comparison of different compounds that is independent of their absolute orientation. Consequently, by placing the carboxyl binding group, the binding site for amido carbonyl, and the Zn atom site in positions determined by ideal binding geometry with the inhibitors' functional groups, it was possible to clearly specify a geometry for the active site of ACE.
144 citations
TL;DR: A highly efficient one-pot procedure for the synthesis of indolines and their homologues based on a domino Cu-catalyzed amidation/nucleophilic substitution reaction has been developed.
94 citations