Novel phenylalanine derived diamides as Factor XIa inhibitors

Smith, Lyman; Orwat, Michael J.; Hu, Zilun; Han, Wei; Wang, Cailan; Rossi, Karen A.; Gilligan, Paul J.; Pabbisetty, Kumar; Osuna, Honey; Corte, James R.; Rendina, Alan R.; Luettgen, Joseph M.; Wong, Pancras C.; Narayanan, R.; Harper, Timothy W.; Bozarth, Jeffrey M.; Crain, Earl J.; Wei, Anzhi; Ramamurthy, Vidhyashankar; Morin, Paul E.; Xin, Baomin; Zheng, Joanna J.; Seiffert, Dietmar; Quan, Mimi L.; Lam, Patrick Y.S.; Wexler, Ruth R.; Pinto, Donald

doi:10.1016/j.bmcl.2015.11.089

Cited by 27 publications

(33 citation statements)

References 27 publications

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“…This inhibitor dose‐dependently reduced thrombosis with an EC 50 value of 2.8 μM. Using a dosing protocol of 0.75 mg/kg (IV bolus) + 3.6 mg/kg/hr (IV infusion), inhibitor 30 prolonged ex vivo APTT by 1.8‐fold and had no effect on the PT, which was consistent with the selective inhibition of the intrinsic coagulation pathway …”

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

confidence: 60%

“…Likewise, inhibitor 31 , which has a cyclopropyl‐amide substituent, has subnanomolar potency toward FXIa with a K i value of 0.36 nM and APTT EC 1.5 x = 1.5 μM (plasma kallikrein K i = 7.5 nM). The reversed diamide 32 was also identified to have FXIa K i = 1.6 nM and APTT EC 1.5 x = 1.0 μM (plasma kallikrein K i = 110 nM) …”

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 Anticoagulsupporting

confidence: 60%

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

confidence: 99%

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%

“…[7][8][9] Of special note is the massive effort that is currently underway to discover active site inhibitors of FXIa, which has realized promising agents. [10][11][12][13][14] For example, two FXIa inhibitors (BMS986177 and EP-7014) are currently in clinical trials. 15 It is likely additional FXIa active site inhibitors will reach clinical trials in the years to come.…”

mentioning

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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“…[11] There is evidence in the literature of the conversion of various cinnamic acids 1 to the corresponding amines 3, by a two-step procedure based on hydrogenation followed by Curtius or Hofmann rearrangements, e. g. in the synthesis of peptidomimetic probes and small molecule pharmaceutical candidates. [13][14][15][16] For example, conversion of 3-bromocinnamic acid required a five step synthesis with an overall yield of 24 %, a method that would still require a de-protection step to afford the free amine. [14] To complement existing strategies, a biocatalytic route requiring mild aqueous conditions was sought, using two enzymes: the cyanobacterial phenylalanine ammonia lyase AvPAL from Anabaena variabilis [8,9,17] and a decarboxylase from Enterococcus faecium, referred to from hereon as EfPheDC.…”

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confidence: 99%

Bi‐enzymatic Conversion of Cinnamic Acids to 2‐Arylethylamines

et al. 2020

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The conversion of carboxylic acids, such as acrylic acids, to amines is a transformation that remains challenging in synthetic organic chemistry. Despite the ubiquity of similar moieties in natural metabolic pathways, biocatalytic routes seem to have been overlooked for this purpose. Herein we present the conception and optimisation of a two‐enzyme system, allowing the synthesis of β‐phenylethylamine derivatives from readily‐available ring‐substituted cinnamic acids. After characterisation of both parts of the reaction in a two‐step approach, a set of conditions allowing the one‐pot biotransformation was optimised. This combination of a reversible deaminating and irreversible decarboxylating enzyme, both specific for the amino acid intermediate in tandem, represents a general method by which new strategies for the conversion of carboxylic acids to amines could be designed.

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Novel phenylalanine derived diamides as Factor XIa inhibitors

Cited by 27 publications

References 27 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

Bi‐enzymatic Conversion of Cinnamic Acids to 2‐Arylethylamines

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