Probing the importance of spacial and conformational domains in captopril analogs for angiotensin converting enzyme activity

Hanessian, Stephen; Reinhold, Ulrich; Saulnier, Michel; Claridge, Stephen

doi:10.1016/s0960-894x(98)00377-1

Cited by 42 publications

(37 citation statements)

References 27 publications

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“…Esters can also serve as directing groups for the cyclopropanation reaction. In the case of the dihydropyrrole 56, a modest degree of syn selectivity is observed (Scheme 3.22) [51]. This sense of diastereoselection is as expected in such a rigid, conformationally biased system.…”

Section: Stereoselective Simmons-smith Cyclopropanations 103mentioning

confidence: 61%

Enantioselective [2+1] Cycloaddition: Cyclopropanation with Zinc Carbenoids

Denmark

Beutner

2001

Cycloaddition Reactions in Organic Synthesis

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Section: Stereoselective Simmons-smith Cyclopropanations 103mentioning

confidence: 61%

Enantioselective [2+1] Cycloaddition: Cyclopropanation with Zinc Carbenoids

Denmark

Beutner

2001

Cycloaddition Reactions in Organic Synthesis

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“…Cis ‐ and trans ‐4,5‐methano‐L‐proline were synthesized according to previously published procedures. The cis isomer was produced from pyroglutamic acid as earlier described by our group, using a one‐pot procedure (i. e. reduction and elimination) for the preparation of the enecarbamate intermediate . The trans isomer was alternately obtained from a TBDPS protected enecarbamate, the bulky silyl ether leading to the trans ‐addition of the methylene …”

Section: Methodsmentioning

confidence: 99%

“…X‐Ray structures of both diastereomers show considerable flattening of the pyrrolidine ring, making it essentially planar in the cis ‐diastereomer, compared to proline itself. We have previously shown the potential utility of these proline methanologues in medicinal chemistry for the first time by the replacement of the proline residue in the antihypertensive drug captopril, an inhibitor of the angiotensin converting enzyme, with cis ‐ and tran s‐4,5‐methanoprolines (Figure B) . Both diastereomers were found to exhibit single digit nM in vitro inhibitory activity as captopril.…”

Section: Introductionmentioning

confidence: 97%

Properties of the Amide Bond Involving Proline 4,5‐methanologues: an Experimental and Theoretical Study

Berger

Chab-Majdalani

Hanessian

2016

Israel Journal of Chemistry

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Herein we disclose a combined experimental and theoretical study on the conformational properties of amide bonds involving diastereomeric 4,5‐methano‐L‐proline congeners as N‐acetyl ethyl esters and dimeric amide ethyl esters as substrates for cyclization to diketopiperazines. The results are discussed in light of density functional theory calculations aimed at delineating the importance of the n→π* stabilization of the trans‐amide conformations. The transitions states for the cyclization of diastereomeric 4,5‐methano‐L‐proline ethyl esters to diketopiperazines were calculated and correlated to the experimental studies.

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“…Compounds 2 and 3 were initially synthesized starting with the L-pyroglutamate ester 14, by a novel acid-mediated destannylative carbocyclization of stereochemically defined iminium ions 15 and 17 respectively, to give the corresponding 4,5-methano-L-prolinol analogues 16 and 18 ( Figure 1A). 5,6 Further steps led to 2 and 3, which were obtained as crystalline compounds. Extended tethers as in respectively.…”

Section: 5-methanoprolines and 56-methanopipecolic Acidsmentioning

confidence: 99%

The Practice of Ring Constraint in Peptidomimetics Using Bicyclic and Polycyclic Amino Acids

2008

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Medicinal chemistry has witnessed major advances with the discovery of small synthetic molecules that mimic natural peptidic substrates. These small synthetic mimics do not undergo proteolytic degradation, an advantage they hold over their natural counterparts. Small synthetic molecules make up a number of life-saving marketed drugs that inhibit certain physiologically relevant proteases. The advent of sophisticated instrumental methods, such as X-ray crystallography and high-field NMR, has played a pivotal role in the design of structure-based enzyme inhibitors. Highly stereocontrolled methods of synthesis have led to a variety of functionally diverse molecules that function as peptidomimetics because they have isosteric subunits not affected by proteolytic enzymes. Further studies to optimize biological activity and achieve desirable pharmacokinetic profiles can eventually lead to drug substances. The practice of constraining natural amino acids like their conformationally rigid counterparts has been highly successful in the design and synthesis of peptidomimetic molecules. With some notable exceptions, structural information gathered from protein X-ray crystallography of therapeutically relevant target enzymes, alone or in complex forms with inhibitor molecules, has been instrumental in the design of peptidomimetics. For example, a significant number have become marketed drugs as antihypertensives and antivirals. Natural products have also been a source of inspiration for the design and synthesis of truncated analogues with the intention of maintaining, or even improving, their biological activities. However, lower molecular weight peptides are not suitable as therapeutic agents because they are subject to rapid amide proteolysis. They are poorly transported to the brain and rapidly excreted through the liver and kidney. Thus, lower molecular weight peptides are eliminated as potential drug substances in clinical practice. A synthetic peptidomimetic is needed that is resistant to cleavage but maintains its biological activity. Conformationally constrained monocyclic and bicyclic unnatural amino acids can be directly incorporated in a potential inhibitor molecule as part of the design element. In this Account, we describe our efforts in the synthesis of constrained azacycles that contain proline or pipecolic acid as an integral part of bicyclic and polycyclic amino acids. We devised syntheses of conformationally biased monocyclic, bicyclic, and polycyclic amino acid analogues, into which pharmacologically or structurally relevant functional groups were incorporated. Stereocontrolled reactions for C-C, C-N, and C-O bond formation had to be implemented on appropriately protected amino acid frameworks. A number of these frameworks provided access to functionally diverse scaffolds for further use as core subunits in more elaborated structures. Specific applications as peptidomimetics of natural substrates for relevant enzymes, such as thrombin, were also pursued, resulting in highly active inhibitors in vitro.

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Probing the importance of spacial and conformational domains in captopril analogs for angiotensin converting enzyme activity

Cited by 42 publications

References 27 publications

Enantioselective [2+1] Cycloaddition: Cyclopropanation with Zinc Carbenoids

Enantioselective [2+1] Cycloaddition: Cyclopropanation with Zinc Carbenoids

Properties of the Amide Bond Involving Proline 4,5‐methanologues: an Experimental and Theoretical Study

The Practice of Ring Constraint in Peptidomimetics Using Bicyclic and Polycyclic Amino Acids

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