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Cardiovascular & Hematological Agents in Medicinal Chemistry


ISSN (Print): 1871-5257
ISSN (Online): 1875-6182

Research Article

Triazol-1-yl Benzamides Promote Anticoagulant Activity via Inhibition of Factor XIIa

Author(s): Rami A. Al-Horani*, Daniel K. Afosah and Madhusoodanan Mottamal

Volume 21, Issue 2, 2023

Published on: 19 December, 2022

Page: [108 - 119] Pages: 12

DOI: 10.2174/1871525721666221031141323

Price: $65


Background: Human factor XIIa (FXIIa) is a plasma serine protease that plays a significant role in several physiological and pathological processes. Animal models have revealed an important contribution of FXIIa to thromboembolic diseases. Remarkably, animals and patients with FXII deficiency appear to have normal hemostasis. Thus, FXIIa inhibition may serve as a promising therapeutic strategy to attain safer and more effective anticoagulation. Very few small molecule inhibitors of FXIIa have been reported. We synthesized and investigated a focused library of triazol-1-yl benzamide derivatives for FXIIa inhibition.

Methods: We chemically synthesized, characterized, and investigated a focused library of triazol- 1-yl benzamide derivatives for FXIIa inhibition. Using a standardized chromogenic substrate hydrolysis assay, the derivatives were evaluated for inhibiting human FXIIa. Their selectivity over other clotting factors was also evaluated using the corresponding substrate hydrolysis assays. The best inhibitor affinity to FXIIa was also determined using fluorescence spectroscopy. Effects on the clotting times (prothrombin time (PT) and activated partial thromboplastin time (APTT)) of human plasma were also studied.

Results: We identified a specific derivative (1) as the most potent inhibitor in this series. The inhibitor exhibited nanomolar binding affinity to FXIIa. It also exhibited significant selectivity against several serine proteases. It also selectively doubled the activated partial thromboplastin time of human plasma.

Conclusion: Overall, this work puts forward inhibitor 1 as a potent and selective inhibitor of FXIIa for further development as an anticoagulant.

Keywords: FXIIa, anticoagulation, triazol-1-yl benzamides, active site inhibitor, small molecule, thrombosis.

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