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

Autor:	Lorthiois E; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Roache J; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Barnes-Seeman D; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Altmann E; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Hassiepen U; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Turner G; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Duvadie R; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Hornak V; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Karki RG; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Schiering N; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Weihofen WA; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Perruccio F; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Calhoun A; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Fazal T; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Dedic D; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Durand C; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Dussauge S; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Fettis K; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Tritsch F; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Dentel C; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Druet A; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Liu D; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Kirman L; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Lachal J; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Namoto K; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Bevan D; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Mo R; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Monnet G; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Muller L; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Zessis R; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Huang X; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Lindsley L; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Currie T; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Chiu YH; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Fridrich C; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Delgado P; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Wang S; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Hollis-Symynkywicz M; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Berghausen J; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Williams E; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Liu H; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Liang G; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Kim H; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Hoffmann P; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Hein A; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Ramage P; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., D'Arcy A; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Harlfinger S; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Renatus M; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Ruedisser S; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Feldman D; Novartis Institutes for BioMedical Research, East Hanover, New Jersey 07396, United States., Elliott J; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Sedrani R; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Maibaum J; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Adams CM; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2020 Aug 13; Vol. 63 (15), pp. 8088-8113. Date of Electronic Publication: 2020 Jul 21.
DOI:	10.1021/acs.jmedchem.0c00279
Abstrakt:	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.
Databáze:	MEDLINE
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