The discovery of glycine and related amino acid-based factor Xa inhibitors

Kohrt, Jeffrey T.; Filipski, Kevin J.; Cody, Wayne L.; Bigge, Christopher F.; La, Frances; Welch, Kathleen M.; Dahring, Tawny K.; Bryant, John W.; Leonard, Daniele; Bolton, Gary L.; Narasimhan, Lakshmi; Zhang, Erli; Peterson, Janet T.; Haarer, Staci; Sahasrabudhe, Vaishali; Janiczek, Nancy; Desiraju, Shrilakshmi; Hena, Mostofa Abu; Fiakpui, Charles Y.; Saraswat, Neerja; Sharma, Raman; Sun, Shaoyi; Maiti, Samarendra N.; Leadley, Robert J.; Edmunds, Jeremy J.

doi:10.1016/j.bmc.2006.02.040

Cited by 15 publications

(8 citation statements)

References 42 publications

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“…45). 234 Compound 271 showed an IC 50 of 33 nM. Alteration of the ring size to cyclopentyl in 273 (fXa IC 50 5 38 nM) or cyclohexyl in 274 (fXa IC 50 5 16 nM) did not significantly affect potency.…”

Section: Factor Xa Inhibitors For Thromboembolic Disorders K 247mentioning

confidence: 98%

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: 98%

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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“…Reaction of the acid chloride with 4‐bromo‐2‐fluoroaniline followed by a Suzuki coupling (9) provided the biaryl P4 group. In the case of the 4‐substituted intermediate 9 , oxidation of the methylsulfide to the methylsulfone was performed with m CPBA in ethyl acetate (14). Deprotection of the t ‐butyl carbamate and TBDMS groups was afforded by 25% (v/v) TFA in methylene chloride which was followed by reaction of the secondary amine with 4‐chlorophenylisocyanate to provide the 4‐chlorophenylurea P1 side chain.…”

Section: Methodsmentioning

confidence: 99%

Structure‐based Drug Design of Pyrrolidine‐1, 2‐dicarboxamides as a Novel Series of Orally Bioavailable Factor Xa Inhibitors

et al. 2007

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A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a D-proline scaffold (1, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.

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The discovery of glycine and related amino acid-based factor Xa inhibitors

Cited by 15 publications

References 42 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

Structure‐based Drug Design of Pyrrolidine‐1, 2‐dicarboxamides as a Novel Series of Orally Bioavailable Factor Xa Inhibitors

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