Synthesis and biological activity of a ketomethylene analog of a tripeptide inhibitor of angiotensin converting enzyme

Almquist, Ronald G.; Chao, Wan‐Ru; Ellis, Marie E.; Johnson, Howard L.

doi:10.1021/jm00186a020

Cited by 100 publications

(47 citation statements)

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“…Keto-ACE is a ketomethylene derivative of a blocked tripeptide substrate, Bz-Phe-Gly-Pro. 41 The IC 50 for N-ACE was 38 to 47 times higher than for C-ACE with Ang I and BK substrates. The reported inhibition of short substrates 28,42 by keto-ACE can be interpreted now as caused by the different affinities of substrates and inhibitors for the two active sites.…”

Section: Discussionmentioning

confidence: 99%

N-Domain–Specific Substrate and C-Domain Inhibitors of Angiotensin-Converting Enzyme

et al. 1998

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Abstract-We used the isolated N-and C-domains of the angiotensin I-converting enzyme (N-ACE and C-ACE; ACE; kininase II) to investigate the hydrolysis of the active 1-7 derivative of angiotensin (Ang) II and inhibition by 5-S-5-benzamido-4-oxo-6-phenylhexanoyl-L-proline (keto-ACE). Ang-(1-7) is both a substrate and an inhibitor; it is cleaved by N-ACE at approximately one half the rate of bradykinin but negligibly by C-ACE. It inhibits C-ACE, however, at an order of magnitude lower concentration than N-ACE; the IC 50 of C-ACE with 100 mol/L Ang I substrate was 1.2 mol/L and the K i was 0.13. While searching for a specific inhibitor of a single active site of ACE, we found that keto-ACE inhibited bradykinin and Ang I hydrolysis by C-ACE in approximately a 38-to 47-times lower concentration than by N-ACE; IC 50 values with C-ACE were 0.5 and 0.04 mol/L. Furthermore, we investigated how Ang-(1-7) acts via bradykinin and the involvement of its B 2 receptor. Ang-(1-7) was ineffective directly on the human bradykinin B 2 receptor transfected and expressed in Chinese hamster ovary cells. However, Ang-(1-7) potentiated arachidonic acid release by an ACE-resistant bradykinin analogue (1 mol/L), acting on the B 2 receptor when the cells were cotransfected with cDNAs of both B 2 receptor and ACE and the proteins were expressed on the plasma membrane of Chinese hamster ovary cells. Thus like other ACE inhibitors, Ang-(1-7) can potentiate the actions of a ligand of the B 2 receptor indirectly by binding to the active site of ACE and independent of blocking ligand hydrolysis. This potentiation of kinins at the receptor level can explain some of the well-documented kininlike actions of Ang-(1-7).(Hypertension. 1998;31:912-917.)

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Section: Discussionmentioning

confidence: 99%

N-Domain–Specific Substrate and C-Domain Inhibitors of Angiotensin-Converting Enzyme

et al. 1998

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“…Kinetic studies of these inhibitors were carried out primarily with HHL used as a substrate. However, both of N1 phosphoryl dipeptides and a ketomethylene tripeptide analogue were reported to behave as competitive inhibitors of ACE when AG I was used as a substrate 20,21). It is possible that K-26 also inhibits ACE competitively with respect to AG I.…”

Section: Discussionmentioning

confidence: 99%

K-26, a novel inhibitor of angiotensin I converting enzyme produced by an Actinomycete K-26.

Yamato¹,

Koguchi²,

Okachi³

et al. 1986

J. Antibiot.

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A novel inhibitor of angiotensin I converting enzyme (ACE), designated K-26, was isolated from the broth filtrate of an actiomycete K-26. K-26 is a water soluble, acidic peptide composed of an equal mol of L-isoleucine, L-tyrosine and l(R)-l-amino-2-(4-hydroxyphenyl)-ethylphosphonic acid. The IC50 of K-26 for ACE inhibition was 6.7 ng/ml when hippuryl-Lhistidyl-L-leucine was used as a substrate of ACE. K-26 possesses hypotensive activity in vivo.Angiotensin I converting enzyme (ACE) has been found to play a critical role in the regulation of blood pressure in man and animals.Ever since the discovery of captoprill1) a specific inhibitor of ACE, and its successful application to the therapy of hypertension, attempts have been made to develop

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“…Keto‐ACE ( 4 , Fig. 1), originally described in 1980, has emerged as a potential lead compound for C‐domain‐specific ACE inhibitors, with a 40–50‐fold greater specificity for this domain compared with the N domain 55,56. Keto‐ACE and its analogues, which were found to inhibit ACE in the nanomolar range, contain a ketomethylene isostere replacement at the scissile bond that is believed to mimic the tetrahedral transition state of the proteolytic reaction 57…”

Section: Synthesis and Selectivity Of Ace Inhibitorsmentioning

confidence: 99%

Development of Domain‐Selective Angiotensin I‐Converting Enzyme Inhibitors

Redelinghuys

Nchinda

Sturrock

2005

Annals of the New York Academy of Sciences

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Somatic angiotensin-converting enzyme (ACE) is an essential component of the renin-angiotensin system and consequently plays a key role in blood pressure and electrolyte homeostasis. Thus, ACE inhibitors are widely used in the treatment of cardiovascular disease, causing a decrease in the production of angiotensin II and an increase in the circulating vasodilator bradykinin. The ectodomain of ACE consists of two parts (N and C domains), each bearing an active site that differs in substrate and inhibitor specificity. Advances in the elucidation of the functional roles of these two domains and an expanded view of the renin-angiotensin system underscore the need for the next generation of domain-selective inhibitors with improved pharmacologic profiles. Moreover, recent breakthroughs in determining the crystal structure of testis ACE (identical to the C domain) and its homologue ACE2 provide new mechanistic insights into the interactions of ACE inhibitors and substrates with active site pockets. This review summarizes the structural basis and recent synthetic chemistry approaches to the development of novel domain-selective inhibitors.

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Synthesis and biological activity of a ketomethylene analog of a tripeptide inhibitor of angiotensin converting enzyme

Cited by 100 publications

References 0 publications

N-Domain–Specific Substrate and C-Domain Inhibitors of Angiotensin-Converting Enzyme

N-Domain–Specific Substrate and C-Domain Inhibitors of Angiotensin-Converting Enzyme

K-26, a novel inhibitor of angiotensin I converting enzyme produced by an Actinomycete K-26.

Development of Domain‐Selective Angiotensin I‐Converting Enzyme Inhibitors

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