Discovery of N-[(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(dimethylcarbamoyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride: A novel, potent and orally active direct inhibitor of factor Xa

Nagata, Tsutomu; Yoshino, Teruo; Haginoya, Noriyasu; Yoshikawa, Kunihiko; Nagamochi, Masatoshi; Kobayashi, Syozo; Komoriya, Satoshi; Yokomizo, Aki; Muto, Ryo; Yamaguchi, Mitsuhiro; Osanai, Ken; Suzuki, Makoto; Kanno, Hideyuki

doi:10.1016/j.bmc.2008.12.037

Cited by 37 publications

(9 citation statements)

References 24 publications

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“…Optimization of 239 also resulted in a series of 4-substituted cyclohexyldiamines, as exemplified by 246 (fXa IC 50 5 2.3 nM, fXa K i 5 2.85 nM, EC 2 Â PT 5 0.33 mM). 220 Compound 246 showed greater than 20,000-fold selectivity against other serine proteases, with the exception of thrombin (900-fold). It also demonstrated low plasma protein binding (72%) and good oral bioavailability in monkeys (F 5 74%).…”

Section: Factor Xa Inhibitors For Thromboembolic Disorders K 247mentioning

confidence: 99%

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

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Thromboembolic diseases are the leading causes of morbidity and mortality in the developed world. Anticoagulants provide effective treatment for venous or arterial thromboembolism. Two coagulation factors, factor Xa (fXa) and thrombin, are the primary targets under active investigation for anticoagulant therapy. fXa, in contrast to the multifunctional roles of thrombin in the coagulation cascade, converts prothrombin to thrombin collectively at the junction of the intrinsic and extrinsic pathway of coagulation. The effectiveness of fXa inhibitors as antithrombotic agents and their potentially reduced bleeding risks may offer superior therapeutic profiles with respect to thrombin inhibitors. After decades of research, many fXa inhibitors are now in the advanced stages of clinical trials. Unlike most reviews, which only provide incremental updates, this review provides an overview of fXa and the medicinal chemistry of its inhibitors. Overviews on coagulation models, antithrombotic therapy, and fXa will be provided, followed by the evolution of the medicinal chemistry of fXa inhibitors over the past few decades.

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Section: Factor Xa Inhibitors For Thromboembolic Disorders K 247mentioning

confidence: 99%

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

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“…A large number of scaffolds have been studied for direct inhibition of FXa including the aminopiperidines [25], piperazines [26], diaminocycloalkanes [27], lactams [28,29], oxazolidinones [30], amino acids (e.g., glycine, proline, and β-aminoproionate) [31,32], anthranilamides [33], isoxazoles [34], pyrazoles [24,35], indazoles [36], indoles [37,38], and dihydropyrazolopyridinones [23,39]. The overall philosophy in the design of these scaffolds is to have a three-component system, which includes a core scaffold and two hydrophobic arms that provide a non-linear geometry considered important for FXa recognition.…”

Section: Introductionmentioning

confidence: 99%

Potent direct inhibitors of factor Xa based on the tetrahydroisoquinoline scaffold

Al‐Horani

Mehta

Desai

2012

European Journal of Medicinal Chemistry

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Direct inhibition of coagulation factor Xa (FXa) carries significant promise for developing effective and safe anticoagulants. Although a large number of FXa inhibitors have been studied, each can be classified as either possessing a highly flexible or a rigid core scaffold. We reasoned that an intermediate level of flexibility will provide high selectivity for FXa considering that its active site is less constrained in comparison to thrombin and more constrained as compared to trypsin. We studied several core scaffolds including 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid for direct FXa inhibition. Using a genetic algorithm-based docking and scoring approach, a promising candidate 23 was identified, synthesized, and found to inhibit FXa with a Ki of 28 μM. Optimization of derivative 23 resulted in the design of a potent dicarboxamide 47, which displayed a Ki of 135 nM. Dicarboxamide 47 displayed at least 1852-fold selectivity for FXa inhibition over other coagulation enzymes and doubled PT and aPTT of human plasma at 17.1 μM and 20.2 μM, respectively, which are comparable to those of clinically relevant agents. Dicarboxamide 47 is expected to serve as an excellent lead for further anticoagulant discovery.

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“…Factor Xa (FacX), which converts prothrombin to thrombin in the coagulation cascade, is a target enzyme for treating thromboembolic disease. Edoxaban and the two other candidates proposed during drug development, 4c and 4d , all bind to the S1 and the S4 pockets of FacX . Edoxaban exhibits both higher affinity to FacX and higher anticoagulant activity than 4c and 4d . − …”

Section: Resultsmentioning

confidence: 99%

“…Edoxaban and the two other candidates proposed during drug development, 4c and 4d , all bind to the S1 and the S4 pockets of FacX . Edoxaban exhibits both higher affinity to FacX and higher anticoagulant activity than 4c and 4d . − …”

Section: Resultsmentioning

confidence: 99%

Scaffold Hopping Transformations Using Auxiliary Restraints for Calculating Accurate Relative Binding Free Energies

Zou

Li²,

Liu³

et al. 2021

J. Chem. Theory Comput.

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In silico screening of drug target interactions is a key part of the drug discovery process.Changes in the drug scaffold via contraction or expansion of rings, the breaking of rings and the introduction of cyclic structures from acyclic structures are commonly applied by medicinal chemists to improve binding affinity and enhance favorable properties of candidate compounds. These processes, commonly referred to as scaffold hopping, are challenging to model computationally. Although relative binding free energy (RBFE) calculations have shown success in predicting binding affinity changes caused by perturbing R-groups attached to a common scaffold, applications of RBFE calculations to modeling scaffold hopping are relatively limited. Scaffold hopping inevitably involves breaking and forming bond interactions of quadratic functional forms, which is highly challenging. A novel method for handling ring opening/closure/contraction/expansion and linker contraction/expansion is presented here. To the best of our knowledge, RBFE calculations on linker contraction/expansion have not been previously reported. The method uses auxiliary restraints to hold the atoms at the ends of a bond in place during the breaking and forming of the bonds. The broad applicability of the method was demonstrated by examining perturbations involving small molecule macrocycles and mutations of proline in proteins. High accuracy was obtained using the method for most of the perturbations studied. Unlike other methods that rely on λ-dependent functional forms for bond interactions, the method presented here can be employed using modern MD software without modification of codes or force field functions.

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Discovery of N-[(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(dimethylcarbamoyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride: A novel, potent and orally active direct inhibitor of factor Xa

Cited by 37 publications

References 24 publications

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Potent direct inhibitors of factor Xa based on the tetrahydroisoquinoline scaffold

Scaffold Hopping Transformations Using Auxiliary Restraints for Calculating Accurate Relative Binding Free Energies

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