Synthesis and pharmacological activity of angiotensin-converting enzyme inhibitors: N-(mercaptoacyl)-4-substituted-(S)-prolines

Smith, Elizabeth M.; Swiss, Gerald F.; Neustadt, Bernard R.; Gold, Elijah H.; Sommer, Jane A.; Brown, Arthur; Chiu, Peter; Moran, Rosa; Sybertz, Edmund J.; Baum, Thomas

doi:10.1021/jm00399a033

Cited by 55 publications

(31 citation statements)

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“…14. Compound 2 was prepared following a method reported by Skiles et al (15), and the classical hydrolysis reaction to obtain the D-captopril was carried out with NaOH 1 N under an atmosphere of argon (16). As there are two asymmetric centers in the molecule, here D-and L-designations refer to absolute stereochemistry at the prolinyl stereocenter (see Fig.…”

Section: Synthesis Of D-captoprilmentioning

confidence: 99%

Coordination Geometries of Metal Ions in D- or L-Captopril-inhibited Metallo-β-lactamases

Heinz

Bauer²,

Wommer

et al. 2003

Journal of Biological Chemistry

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D-and L-captopril are competitive inhibitors of metallo-␤-lactamases. For the enzymes from Bacillus cereus (BcII) and Aeromonas hydrophila (CphA), we found that the mononuclear enzymes are the favored targets for inhibition. By combining results from extended x-ray absorption fine structure, perturbed angular correlation of ␥-rays spectroscopy, and a study of metal ion binding, we derived that for Cd(II) 1 -BcII, the thiolate sulfur of D-captopril binds to the metal ion located at the site defined by three histidine ligand residues. This is also the case for the inhibited Co(II) 1 and Co(II) 2 enzymes as observed by UV-visible spectroscopy. Although the single metal ion in Cd(II) 1 -BcII is distributed between both available binding sites in both the uninhibited and the inhibited enzyme, Cd(II) 1 -CphA shows only one defined ligand geometry with the thiolate sulfur coordinating to the metal ion in the site composed of 1 Cys, 1 His, and 1 Asp. CphA shows a strong preference for D-captopril, which is also reflected in a very rigid structure of the complex as determined by perturbed angular correlation spectroscopy. For BcII and CphA, which are representatives of the metallo-␤-lactamase subclasses B1 and B2, we find two different inhibitor binding modes.Metallo-␤-lactamases confer antibiotic resistance to bacteria by catalyzing the hydrolysis of ␤-lactam antibiotics, including carbapenems. This relatively new form of resistance is spreading and thereby escaping the effective inhibitors developed to fight the better known serine-␤-lactamases. For all metallo-␤-lactamases investigated, structurally similar enzyme active sites comprising two zinc binding sites are reported. For Bacillus cereus metallo-␤-lactamase (BcII), 1 one metal-binding site contains three His (H-site); the other one contains 1 Asp, 1 Cys, and 1 His as the metal ligating residues (DCH site) as derived from x-ray crystallography (1). For CphA, 1 His from the H-site (His-116) is supposed to be replaced by an Asn (2). Various thiol-carboxylate compounds were identified as potent inhibitors (3). The active site binding of thiomandelic acid to BcII was studied by NMR spectroscopy (4), whereas the binding of 2-[5-(1-tetrazolylmethyl)thien-3-yl]-N-[2-(mercaptomethyl)-4-(phenylbutrylglycine)] to the enzyme from Pseudomonas aeruginosa (IMP-1) was characterized by x-ray crystallography (5). With both approaches, the inhibited binuclear zinc enzymes were studied. Both studies agree in a bridging role of the metal-bound sulfur of the inhibitor, whereas the carboxylate group of the inhibitors binds to an accessible amino acid, thus stabilizing the complex. Other known inhibitory compounds are 2,3-(S,S)-disubstituted succinic acids for IMP-1 (6) or moxalactam and cefoxitin for CphA (7). The latter compounds lead to irreversible inactivation of the enzyme by the hydrolyzed reaction products.The structural investigation of D-and L-captopril binding presented here is based on results obtained from enzyme kinetic and thermodynamic studies. Captopril is known as an ...

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Section: Synthesis Of D-captoprilmentioning

confidence: 99%

Coordination Geometries of Metal Ions in D- or L-Captopril-inhibited Metallo-β-lactamases

Heinz

Bauer²,

Wommer

et al. 2003

Journal of Biological Chemistry

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“…LCaptopril exhibited an IC 50 of 3.3 µM and a measured Ki of 1.8 µM (competitive). Again, the binding is stereoselective, as D-captopril 15 was an order of magnitude less potent, with an IC 50 of 42.0 µM. Table 3 shows several other compounds that were screened versus the DapE enzyme.…”

mentioning

confidence: 99%

Inhibitors of bacterial N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) and demonstration of in vitro antimicrobial activity

Gillner

Armoush

Holz

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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“…In vivo ACE inhibitory activity was determined by the reported procedure (Smith et al, 1988). Sprague-Dawley rats were anesthetized with urethane.…”

Section: In Vivo Testingmentioning

confidence: 99%

“…Pyroglutamic acid itself, or in a modified manner, has been utilized not only for total synthesis of many bioactive natural products such as (-)bulgecinine (Ohta et al, 1988;Panday and Langlois, 1997), anatoxin (Peterson et al, 1984) etc., but also for synthetic bioactive molecules such as fosinopril (Krapcho et al, 1988;Smith et al, 1988Smith et al, , 1989Alexandrou and Liakopoulou-Kyriakides, 1990; Thottahil et al, 1986), an ACE inhibitor. Pyroglutamic acid has a lactam NH as well as two differential carbonyl groups.…”

Section: Introductionmentioning

confidence: 99%

“…All these are proline derivatives with appropriate N-acylation. Based on SAR and hypothetical model for ACE binding sites, it has been observed that replacement of proline part of captopril or enalapril with 4-substituted prolines (Krapcho et al, 1988;Smith et al, 1988Smith et al, , 1989Alexandrou and Liakopoulou-Kyriakides, 1990;Thottahil et al, 1986) and 5-oxoprolines (Imaki et al, 1981) led to significant increase in ACE inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of N-[3′-(acetylthio)alkanoyl] and N-[3′-mercaptoalkanoyl]-4-α(s)-(phenylmethyl) pyroglutamic acids and prolines as potent ACE inhibitors

Panday

Dikshit

2009

Med Chem Res

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Angiotensin converting enzyme (ACE) inhibitors have emerged as a revolution in antihypertensive therapy. Introduction of captopril, the first rationally designed ACE inhibitor, has encouraged researchers all over the world to design and synthesize target molecules controlling hypertension based on these lines. It has been observed that replacing proline part of captopril with 4-substituted prolines or 5-oxo-prolines led to significant enhancement in ACE inhibitory activity, and this observation prompted us to design and synthesize N-acyl 4-substituted pyroglutamates and prolinates with the objective of developing therapeutically better ACE inhibitors. Herein we describe an easy approach for N-acylation of 4-a(S)-(phenylmethyl) pyroglutamates with the aim of synthesizing N-[3 0 -(acetylthio)alkanoyl] and N-[3 0 -mercaptoalkanoyl]-4-a-(s)-(phenylmethyl) pyroglutamic acids and prolines as ACE inhibitors.

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Synthesis and pharmacological activity of angiotensin-converting enzyme inhibitors: N-(mercaptoacyl)-4-substituted-(S)-prolines

Cited by 55 publications

References 0 publications

Coordination Geometries of Metal Ions in D- or L-Captopril-inhibited Metallo-β-lactamases

Coordination Geometries of Metal Ions in D- or L-Captopril-inhibited Metallo-β-lactamases

Inhibitors of bacterial N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) and demonstration of in vitro antimicrobial activity

Synthesis of N-[3′-(acetylthio)alkanoyl] and N-[3′-mercaptoalkanoyl]-4-α(s)-(phenylmethyl) pyroglutamic acids and prolines as potent ACE inhibitors

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