Potent Thrombin Inhibitors That Probe the S<sub>1</sub>‘ Subsite:  Tripeptide Transition State Analogues Based on a Heterocycle-Activated Carbonyl Group

Costanzo, Michael J.; Maryanoff, Bruce E.; Hecker, Leonard R.; Schott, Mary R.; Yabut, Stephen C.; Zhang, Han‐Cheng; Andrade‐Gordon, Patricia; Kauffman, Jack A.; Lewis, Joan M.; Krishnan, Rahul; Tulinsky, A.

doi:10.1021/jm9603274

Cited by 66 publications

(41 citation statements)

References 25 publications

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“…The structures of thrombin complexes with thiazole inhibitors similar to RWJ-51438 have been reported. The comparison of RWJ-50353±thrombin (Matthews et al, 1996;Costanzo et al, 1996) and MOL-168± thrombin (Charles et al, 1999) with the complex structure studied here shows similarities in the binding of the inhibitor to the protein. However, differences in binding of RWJ-51438 to thrombin are apparent owing to the presence of the carboxylate substituent on the benzothiazole (Bzt) ring.…”

Section: P1 H H H Interactionsmentioning

confidence: 52%

“…Two examples of such compounds are benzothiazoles I and II (Table 1). The use of a heterocycle at the P1 H position imparts the necessary electrophilicity to the arginine carbonyl moiety of the inhibitor (Edwards et al, 1992;Tsutsumi et al, 1994;Costanzo et al, 1996;Matthews et al, 1996;Recacha et al, 1999). An advantage of such heterocycleactivated ligands over those with other electrophilic ketones is the availability of heterocycles that can be incorporated into a peptidyl ketone, allowing modulation of the physiochemical properties.…”

Section: Introductionmentioning

confidence: 99%

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Structure of human α-thrombin complexed with RWJ-51438 at 1.7 Å: unusual perturbation of the 60A–60I insertion loop

Recacha

Costanzo²,

Maryanoff³

et al. 2000

Acta Crystallogr D Biol Cryst

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The three-dimensional structure of the ternary complex consisting of human -thrombin, hirugen and the active-site inhibitor RWJ-51438 has been determined at 1.7 A Ê resolution. The crystals of the complex belong to the orthorhombic space group P2 1 2 1 2, with unit-cell parameters a = 62.98, b = 117.52, c = 47.99 A Ê . The re®ned R and R free values are 0.196 and 0.232, respectively. The ketone carbonyl group of the inhibitor is covalently linked to the hydroxyl O atom of Ser195, forming a tetrahedral intermediate hemiketal structure; the benzothiazole ring N atom of RWJ-51438 forms a hydrogen bond with His57. Surprisingly, the carboxylate substituent on the benzothiazole group forms salt bridges with Lys60F NZ and the NZ of the symmetry-related residues Lys236 and Lys240, which introduces steric effects that perturb the 60A±60I insertion loop, especially at residues Trp60D and Phe60H.

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Section: P1 H H H Interactionsmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Structure of human α-thrombin complexed with RWJ-51438 at 1.7 Å: unusual perturbation of the 60A–60I insertion loop

Recacha

Costanzo²,

Maryanoff³

et al. 2000

Acta Crystallogr D Biol Cryst

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“…Thus, modulation of the ring substituents may be utilized to achieve discrimination between different enzymes of the same subclass. Constanzo et al [157] have performed crystallographic studies on a-keto benzothiazoles which showed favourable hydrophobic interactions between the heterocyclic aromatic moiety and residues in the S¢ subsite of thrombin (Trp60D and Tyr60A), Trp60D stacks in a perpendicular fashion with the aromatic ring of the benzothiazole, whilst the nitrogen atom of the benzothiazole moiety is shown to H-bond to the imidazole nitrogen of His 57 (analogous to that reported by Edwards et al [149]). The hydrophobic interactions are believed to confer selectvity for thrombin in comparison with trypsin and plasmin.…”

Section: Other Peptide-based Serine Protease Inhibitorsmentioning

confidence: 74%

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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“…A group at Johnson & Johnson resumed earlier developments [170,171] of a thrombin inhibitor that probes the S 1 ′ binding site [172]. The design of these inhibitors is based on the idea of substituting the X in the known thrombin recognition motif D-Phe-Pro-Arg-X (see also PPACK,9) with heterocycles that would (i) increase the electrophilicity of the arginine carbonyl such that it would form a hemiketal adduct with the γ-oxygen of the activesite Ser195 and (ii) extend interactions with thrombin into the S 1 ′ binding site.…”

Section: New Inhibitors -Old Principlesmentioning

confidence: 99%

Direct thrombin inhibitors – a survey of recent developments

Schwienhorst¹

2006

Cell. Mol. Life Sci.

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Thrombin is a plasma serine protease that plays a key role in coagulation and hemostasis but also in thromboembolic diseases. Direct thrombin inhibitors could, therefore, be beneficial for future anticoagulant therapy in the prophylaxis of venous and arterial thrombosis as well as myocardial infarction. However, development of direct thrombin inhibitors has brought researchers more heartache than success. The most recent setback came this year when AstraZeneca withdrew Ximelagatran, the first orally bioavailable direct thrombin inhibitor that had received regulatory approval (France, 2003), after reports of serious hepatoxicity in a fraction of patients. This review describes the status of direct thrombin inhibitors, focusing on drug candidates that are at present in clinical trials. In addition, some more recent research strategies in the design of novel direct thrombin inhibitors are discussed, which may very well contribute to future developments of potent anticoagulants.

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Potent Thrombin Inhibitors That Probe the S₁‘ Subsite: Tripeptide Transition State Analogues Based on a Heterocycle-Activated Carbonyl Group

Cited by 66 publications

References 25 publications

Structure of human α-thrombin complexed with RWJ-51438 at 1.7 Å: unusual perturbation of the 60A–60I insertion loop

Structure of human α-thrombin complexed with RWJ-51438 at 1.7 Å: unusual perturbation of the 60A–60I insertion loop

Strategies for the inhibition of serine proteases

Direct thrombin inhibitors – a survey of recent developments

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Potent Thrombin Inhibitors That Probe the S1‘ Subsite: Tripeptide Transition State Analogues Based on a Heterocycle-Activated Carbonyl Group

Cited by 66 publications

References 25 publications

Structure of human α-thrombin complexed with RWJ-51438 at 1.7 Å: unusual perturbation of the 60A–60I insertion loop

Structure of human α-thrombin complexed with RWJ-51438 at 1.7 Å: unusual perturbation of the 60A–60I insertion loop

Strategies for the inhibition of serine proteases

Direct thrombin inhibitors – a survey of recent developments

Contact Info

Product

Resources

About

Potent Thrombin Inhibitors That Probe the S₁‘ Subsite: Tripeptide Transition State Analogues Based on a Heterocycle-Activated Carbonyl Group