Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties

Pinto, Donald; Smallheer, Joanne M.; Corte, James R.; Austin, Erin J.D.; Wang, Cailan; Fang, Tianan; Smith, Lyman; Rossi, Karen A.; Bozarth, Jeffrey M.; Zhang, Ge; Wei, Anzhi; Ramamurthy, Vidhyashankar; Sheriff, S.; Myers, Joseph E.; Morin, Paul E.; Luettgen, Joseph M.; Seiffert, Dietmar; Quan, Mimi L.; Wexler, Ruth R.

doi:10.1016/j.bmcl.2015.01.028

Cited by 39 publications

(29 citation statements)

References 25 publications

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“…This inhibitor increased the clotting time in the APTT assay by 1.5‐fold at a plasma concentration of 8.6 μM. This inhibitor also demonstrated good selectivity over FVIIa ( K i > 13,000 nM), FIXa ( K i > 60,000 nM), FXa ( K i = 1500 nM), thrombin ( K i > 15,000 nM), trypsin ( K i > 6200 nM), plasma kallikrein ( K i = 240 nM), tissue kallikrein ( K i > 30,000 nM), chymotrypsin ( K i = 1300 nM), plasmin ( K i > 41,000 nM), and tPA ( K i = 17,000 nM) …”

Section: Factor Xia (Fxia): An Emerging Protein Target For Anticoagulmentioning

confidence: 88%

“…In subsequent studies, Pinto et al. reported on a series of structure‐based efforts to enhance the antithrombotic profile of 53 . All efforts were focused on improving the selectivity as well as oral bioavailability by using different less basic functionalities that bind to the S1 pocket.…”

Section: Factor Xia (Fxia): An Emerging Protein Target For Anticoagulmentioning

confidence: 99%

“…122 In subsequent studies, Pinto et al reported on a series of structure-based efforts to enhance the antithrombotic profile of 53. 123 All efforts were focused on improving the selectivity as well as oral bioavailability by using different less basic functionalities that bind to the S1 pocket. Accordingly, it was found that inhibitor 54 ( Figure 14 of inhibitors 55 and 56 to further improve the potency, stability, and solubility of this chemotype.…”

Section: Imidazole-containing Derivativesmentioning

confidence: 99%

“…This inhibitor increased the clotting time in the APTT assay by 1.5-fold at a plasma concentration of 5.3 M. Interestingly, removing the chlorine atom from the imidazole moiety led to inhibitor 55, which had a FXIa K i value of 6.7 nM, a volume of distribution of 3.4 L/kg, a clearance value of 20 mL/min/kg, a T 0.5 of 2.4 hr, and an oral bioavailability of ∼10.4% in dogs. This inhibitor increased the clotting time in the APTT assay by 1.5-fold at a plasma concentration of 8.6 M. This inhibitor also demonstrated good selectivity over FVIIa (K i > 13,000 nM), FIXa (K i > 60,000 nM), FXa (K i = 1500 nM), thrombin (K i > 15,000 nM), trypsin (K i > 6200 nM), plasma kallikrein (K i = 240 nM), tissue kallikrein (K i > 30,000 nM), chymotrypsin (K i = 1300 nM), plasmin (K i > 41,000 nM), and tPA (K i = 17,000 nM) 123. Along those lines, Hu et al reported the continued structural optimization efforts at the P1 ′ and P2 ′ regions…”

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confidence: 99%

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Recent advances in the discovery and development of factor XI/XIa inhibitors

Al‐Horani

Afosah

2018

Medicinal Research Reviews

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Factor XIa (FXIa) is a serine protease homodimer that belongs to the intrinsic coagulation pathway. FXIa primarily catalyzes factor IX activation to factor IXa, which subsequently activates factor X to factor Xa in the common coagulation pathway. Growing evidence suggests that FXIa plays an important role in thrombosis with a relatively limited contribution to hemostasis. Therefore, inhibitors targeting factor XI (FXI)/FXIa system have emerged as a paradigm-shifting strategy so as to develop a new generation of anticoagulants to effectively prevent and/or treat thromboembolic diseases without the life-threatening risk of internal bleeding. Several inhibitors of FXI/FXIa proteins have been discovered or designed over the last decade including polypeptides, active site peptidomimetic inhibitors, allosteric inhibitors, antibodies, and aptamers. Antisense oligonucleotides (ASOs), which ultimately reduce the hepatic biosynthesis of FXI, have also been introduced. A phase II study, which included patients undergoing elective primary unilateral total knee arthroplasty, revealed that a specific FXI ASO effectively protects patients against venous thrombosis with a relatively limited risk of bleeding. Initial findings have also demonstrated the potential of FXI/FXIa inhibitors in sepsis, listeriosis, and arterial hypertension. This review highlights various chemical, biochemical, and pharmacological aspects of FXI/FXIa inhibitors with the goal of advancing their development toward clinical use.

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Section: Factor Xia (Fxia): An Emerging Protein Target For Anticoagulmentioning

confidence: 88%

Section: Factor Xia (Fxia): An Emerging Protein Target For Anticoagulmentioning

confidence: 99%

Section: Imidazole-containing Derivativesmentioning

confidence: 99%

mentioning

confidence: 99%

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Recent advances in the discovery and development of factor XI/XIa inhibitors

Al‐Horani

Afosah

2018

Medicinal Research Reviews

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“…Cyclization of 2e under heating PPA conditions provided 4-hydroxyquinolinone amino acid 2f in near quantitative yield. This amino acid was reacted with Nhydroxysuccinimide ester 2h, which was prepared from 2g, 21 to give the penultimate acid 2i. Final amide coupling under mixed anhydride conditions afforded 13 in good overall yield (26%).…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2′ Moiety

Wong

Gilligan

et al. 2015

ACS Med. Chem. Lett.

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Structure−activity relationship optimization of phenylalanine P1′ and P2′ regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2′ group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC 2x of 1.0 μM. Dosedependent efficacy (EC 50 of 0.53 μM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.

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Anticoagulants

Quan

Glunz

Luettgen

2021

Burger's Medicinal Chemistry and Drug Discovery

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Although blood circulation is highly regulated, dysfunctional activities resulting from either deficient or excessive coagulation have serious health consequences. Insufficient clotting can lead to prolonged bleeding and hemophilia‐related conditions. Over activation of coagulation can lead to thrombosis‐related disorders, such as deep venous thrombosis, pulmonary embolism, and stroke, which together are a major cause of morbidity and mortality. Studies of the biological pathways leading to coagulation, and the resultant development and refinement of the coagulation cascade, have identified many potential biological targets for therapeutic intervention. The major challenge regarding the treatment and prevention of thromboembolic diseases is the requirement for effective anticoagulant therapy without exposing patients to an increased risk of bleeding. Preclinical and clinical evaluations of anticoagulant agents highlight this efficacy/bleeding dichotomy. This article presents the medicinal chemistry efforts leading to the discovery of inhibitors of the coagulation cascade, resulting in marketed thrombin and Factor Xa inhibitors. Also reported is the progress toward identifying emerging anticoagulants.

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Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties

Cited by 39 publications

References 25 publications

Recent advances in the discovery and development of factor XI/XIa inhibitors

Recent advances in the discovery and development of factor XI/XIa inhibitors

Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2′ Moiety

Anticoagulants

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