Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker

Corte, James R.; Fang, Tianan; Osuna, Honey; Pinto, Donald; Rossi, Karen A.; Myers, Joseph E.; Sheriff, S.; Lou, Zhen; Zheng, Joanna J.; Harper, Timothy W.; Bozarth, Jeffrey M.; Wu, Yiming; Luettgen, Joseph M.; Seiffert, Dietmar; Decicco, Carl P.; Wexler, Ruth R.; Quan, Mimi L.

doi:10.1021/acs.jmedchem.6b01460

Cited by 39 publications

(41 citation statements)

References 67 publications

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“…However, both inhibitors inhibited plasma kallikrein with K i values of 16 and 70 nM, respectively. It is important to mention here that the crystal structure of inhibitor 60 with FXIa (PDB ID: 5TKU) confirmed the H‐bond interaction between the installed amide linker and the carbonyl of Leu41 …”

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

confidence: 60%

“…In the FXIa inhibition/binding assay, all analogs inhibited the enzyme with K i values within the range of 42–3920 nM. Among them, only two inhibitors had potent impact on clotting time in the APTT assay, namely inhibitors 58 and 59 (Figure ), which increased the APTT by 1.5‐fold at plasma concentrations of 27 μM (FXIa K i = 42 nM) and 34 μM (FXIa K i = 68 nM), respectively …”

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

confidence: 99%

“…To improve the FXIa binding affinity and the APTT potency of inhibitor 56, Corte et al. preorganized the inhibitor's conformation via the formation of a macrocyclic ring . Macrocyclization has been recognized in drug discovery and development as an important chemical strategy to improve the chemical stability, binding affinity, selectivity, and pharmacokinetic properties of acyclic peptides or peptidomimetics .…”

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

confidence: 99%

“…The two inhibitors had high clearance values of 23 and 15 mL/hr/kg, respectively, short half‐lives of ∼1 hr, small volumes of distribution of 1.8 and 0.8 L/kg, respectively, low area under the curve (AUC) values of 2.5 and 21 nM/hr, respectively, high dog liver microsomal stability ( T 0.5 > 120 min), and high dog protein binding of ∼90%. They both had very poor oral bioavailability of 1% and 6%, respectively, at tested doses . Therefore, these two inhibitors were subject to further structural modifications that focused on the imidazole ring, the macrocyclic amide linker, and the P1 tetrazole‐containing group .…”

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

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: 60%

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

confidence: 99%

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

confidence: 99%

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

confidence: 99%

See 2 more Smart Citations

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

Al‐Horani

Afosah

2018

Medicinal Research Reviews

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“…In fact, active site inhibitors (also called orthosteric inhibitors) are being actively pursued against several coagulation factors including factor XIa (FXIa), factor VIIa (FVIIa), and factor IXa (FIXa) . Of special note is the massive effort that is currently underway to discover active site inhibitors of FXIa, which has realized promising agents . For example, two FXIa inhibitors (BMS986177 and EP‐7014) are currently in clinical trials .…”

Section: Introductionmentioning

confidence: 99%

A synthetic heparin mimetic that allosterically inhibits factor XIa and reduces thrombosis in vivo without enhanced risk of bleeding

Al‐Horani

Abdelfadiel

Afosah

et al. 2019

Journal of Thrombosis and Haemostasis

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Background Human factor XIa (FXIa) is an actively pursued target for development of safer anticoagulants. Our long‐standing hypothesis has been that allosterism originating from heparin‐binding site(s) on coagulation enzymes is a promising approach to yield safer agents. Objectives To develop a synthetic heparin mimetic as an inhibitor of FXIa so as to reduce clot formation in vivo but not carry high bleeding risk. Methods We employed a gamut of methods involving synthetic chemistry, biophysical biochemistry, enzyme assays, blood and plasma coagulation assays, and in vivo thrombosis models in this work. Results Sulfated chiro‐inositol (SCI), a non‐saccharide mimetic of heparin, was synthesized in three steps in overall yields of >50%. SCI inhibited FXIa with potency of 280 nmol/L and preferentially engaged FXIa's heparin‐binding site to conformationally alter its active site. SCI inhibition of FXIa could be rapidly reversed by common antidotes, such as protamine. SCI preferentially prolonged plasma clotting initiated with recalcification, rather than thromboplastin, alluding to its intrinsic pathway‐based mechanism. Human blood thromboelastography indicated good ex vivo anticoagulation properties of SCI. Rat tail bleeding and maximum‐dose‐tolerated studies indicated that no major bleeding or toxicity concerns for SCI suggesting a potentially safer anticoagulation outcome. FeCl3‐induced arterial and thromboplastin‐induced venous thrombosis model studies in the rat showed reduced thrombus formation by SCI at 250 μg/animal, which matched enoxaparin at 2500 μg/animal. Conclusions Overall, SCI is a highly promising, allosteric inhibitor of FXIa that induces potent anticoagulation in vivo. Further studies are necessary to assess SCI in animal models mimicking human clinical indications.

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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 Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker

Cited by 39 publications

References 67 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

A synthetic heparin mimetic that allosterically inhibits factor XIa and reduces thrombosis in vivo without enhanced risk of bleeding

Anticoagulants

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