1. Academic Validation
  2. Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach

Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach

  • J Med Chem. 2020 Aug 13;63(15):8088-8113. doi: 10.1021/acs.jmedchem.0c00279.
Edwige Lorthiois 1 James Roache 2 David Barnes-Seeman 2 Eva Altmann 1 Ulrich Hassiepen 1 Gordon Turner 2 Rohit Duvadie 2 Viktor Hornak 2 Rajeshri G Karki 2 Nikolaus Schiering 1 Wilhelm A Weihofen 2 Francesca Perruccio 1 Amy Calhoun 2 Tanzina Fazal 2 Darija Dedic 1 Corinne Durand 1 Solene Dussauge 1 Kamal Fettis 1 Fabien Tritsch 1 Celine Dentel 1 Adelaide Druet 1 Donglei Liu 2 Louise Kirman 2 Julie Lachal 1 Kenji Namoto 1 Douglas Bevan 2 Rose Mo 2 Gabriela Monnet 1 Lionel Muller 1 Richard Zessis 2 Xueming Huang 2 Loren Lindsley 2 Treeve Currie 2 Yu-Hsin Chiu 2 Cary Fridrich 2 Peter Delgado 2 Shuangxi Wang 2 Micah Hollis-Symynkywicz 2 Joerg Berghausen 1 Eric Williams 2 Hong Liu 2 Guiqing Liang 2 Hyungchul Kim 2 Peter Hoffmann 2 Andreas Hein 1 Paul Ramage 1 Allan D'Arcy 1 Stefanie Harlfinger 1 Martin Renatus 1 Simon Ruedisser 1 David Feldman 3 Jason Elliott 2 Richard Sedrani 1 Juergen Maibaum 1 Christopher M Adams 2
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
  • 2 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
  • 3 Novartis Institutes for BioMedical Research, East Hanover, New Jersey 07396, United States.
Abstract

The serine Protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation 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 submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a 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 subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.

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