Peptidyl α-keto thiazole as potent thrombin inhibitors

Akiyama, Yoshihisa; Tsutsumi, Seiji; Hatsushiba, Emiko; Ohuchi, Shokichi; Okonogi, Tsuneo

doi:10.1016/s0960-894x(97)00057-7

Cited by 23 publications

(10 citation statements)

References 16 publications

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“…Results from this work showed that PEP displays a much greater tolerance for variation in the heterocyclic group, for example, a-keto thiazoles and benzoxazoles had similar activity (in contrast to results obtained with PPE and HNE [151]); however, it was shown that the critical requirement for the bnitrogen in the heterocyclic ring, observed with HNE, was also necessary for PEP. The same group has also shown that a-keto thiazoles had excellent activity against thrombin and trypsin [155]. More extensive SAR studies have shown that variation of the P 1 basic residue (Arg, Lys or homoLys) resulted in a reduction in potency for thrombin in comparison with trypsin.…”

Section: Other Peptide-based Serine Protease Inhibitorsmentioning

confidence: 97%

Strategies for the inhibition of serine proteases

Walker¹,

Lynas²

2001

CMLS, Cell. Mol. Life Sci.

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Serine proteases have been shown to play a multifarious role in health and disease. As a result, there has been considerable interest in the design and development of synthetic inhibitors of these enzymes. In view of their diverse roles in biological processing events, one of the great challenges in such endeavours has been the need to produce compounds with exquisite selectivity. Inhibitor design has been broadly guided by the use of either peptide- or heterocyclic-based compounds, designed to exploit the known substrate specificity characteristics of individual enzymes. This review describes the thinking and strategies employed in such efforts.

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Section: Other Peptide-based Serine Protease Inhibitorsmentioning

confidence: 97%

Strategies for the inhibition of serine proteases

Walker¹,

Lynas²

2001

CMLS, Cell. Mol. Life Sci.

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“…Since Edwards' disclosure of ␣-keto heterocycles as effective protease inhibitors, a number of enzyme inhibitors have been described on the basis of analogous design principles (60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70). The inhibitors developed herein define additional features that may contribute independently to binding affinity which, when Abbreviation: FAAH, fatty acid amide hydrolase.…”

mentioning

confidence: 99%

Exceptionally potent inhibitors of fatty acid amide hydrolase: The enzyme responsible for degradation of endogenous oleamide and anandamide

Boger

Sato

Lerner

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

263

264

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The development of exceptionally potent inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid), and anandamide (an endogenous ligand for cannabinoid receptors) is detailed. The inhibitors may serve as useful tools to clarify the role of endogenous oleamide and anandamide and may prove to be useful therapeutic agents for the treatment of sleep disorders or pain. The combination of several features-an optimal C12-C8 chain length, -unsaturation introduction at the corresponding arachidonoyl ⌬ 8,9 ͞⌬ 11,12 and oleoyl ⌬ 9,10 location, and an ␣-keto N4 oxazolopyridine with incorporation of a second weakly basic nitrogen provided FAAH inhibitors with Kis that drop below 200 pM and are 10 2 -10 3 times more potent than the corresponding trifluoromethyl ketones.

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“…It is acknowledged that at the time our patents 29,30 were published describing these lysine derivatives, a number of publications appeared on related heterocycle-activated ketone derivatives and R-keto acids 16,17,31 and derivatives of the D-Phe-Pro-Arg motif. 26,27,[32][33][34] Some of these papers describe the substitution of a lysine for an arginine group. More publications appeared in recent years on this subject focusing on potent thrombin inhibition and selectivity but with limited data on pharmacokinetic behavior.…”

Section: Resultsmentioning

confidence: 99%

Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics

Adang¹,

Man²,

Vogel³

et al. 2002

J. Med. Chem.

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Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED(50) was 5.4 nmol/kg.min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.

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Peptidyl α-keto thiazole as potent thrombin inhibitors

Cited by 23 publications

References 16 publications

Strategies for the inhibition of serine proteases

Strategies for the inhibition of serine proteases

Exceptionally potent inhibitors of fatty acid amide hydrolase: The enzyme responsible for degradation of endogenous oleamide and anandamide

Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics

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