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Structure-based design and pre-clinical characterization of selective and orally bioavailable Factor XIa inhibitors: Demonstrating the power of an integrated S1 protease family approach

Lorthiois, Edwige and Roache, James and Barnes, David and Altmann, Eva and Hassiepen, Ulrich and Turner, Gordon and Duvadie, Rohit and Hornak, Viktor and Karki, Rajeshri and Schiering, Nikolaus and Weihofen, Wilhelm and Perruccio, Francesca and Calhoun, Amy and Fazal, Tanzina and Dedic, Darija and Durand, Corinne and Dussauge, Solene and Fettis, Kamal and Tritsch, Fabien and Dentel, Celine and Druet, Adelaide and Liu, Donglei and Kirman, Louise and Lachal, Julie and Namoto, Kenji and Bevan Jr, Doug and Mo, Ruowei and Monnet, Gabriela and Muller, Lionel and Zessis, Richard and Huang, Xueming and Lindsley, Loren and Currie, Treeve and Chiu, Yu-Hsin and Fridrich, Cary and Delgado, Pete and Wang, Shuangxi and Hollis-Symynkywicz, Micah and Berghausen, Joerg and Williams, Eric and Liu, Hong and Liang, Guiqing and Kim, Hyungchul and Hoffmann, Peter and Hein, Andreas and Ramage, Paul and D'Arcy, Allan and Harlfinger, Stephanie and Renatus, Martin and Ruedisser, Simon and Feldman, David and Elliott, Jason and Sedrani, Richard and Maibaum, Juergen Klaus and Adams, Christopher (2020) Structure-based design and pre-clinical characterization of selective and orally bioavailable Factor XIa inhibitors: Demonstrating the power of an integrated S1 protease family approach. Journal of medicinal chemistry, 63 (15). pp. 8088-8113. ISSN 1520-4804; 0022-2623

Abstract

The serine protease Factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anti-coagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement Factor D inhibitor and exhibited sub-micromolar FXIa activity and an encouraging ADME profile while being devoid of peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1` pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with sub-nanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a pre-clinical PK profile consistent with bid dosing in patients.

Item Type: Article
Date Deposited: 16 Oct 2020 00:45
Last Modified: 16 Oct 2020 00:45
URI: https://oak.novartis.com/id/eprint/40904

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