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


Journal

Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531

Informations de publication

Date de publication:
13 08 2020
Historique:
pubmed: 20 6 2020
medline: 26 11 2020
entrez: 20 6 2020
Statut: ppublish

Résumé

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

Identifiants

pubmed: 32551603
doi: 10.1021/acs.jmedchem.0c00279
doi:

Substances chimiques

Factor Xa Inhibitors 0
Factor XIa EC 3.4.21.27

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

8088-8113

Auteurs

Edwige Lorthiois (E)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

James Roache (J)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

David Barnes-Seeman (D)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Eva Altmann (E)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Ulrich Hassiepen (U)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Gordon Turner (G)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Rohit Duvadie (R)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Viktor Hornak (V)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Rajeshri G Karki (RG)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Nikolaus Schiering (N)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Wilhelm A Weihofen (WA)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Francesca Perruccio (F)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Amy Calhoun (A)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Tanzina Fazal (T)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Darija Dedic (D)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Corinne Durand (C)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Solene Dussauge (S)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Kamal Fettis (K)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Fabien Tritsch (F)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Celine Dentel (C)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Adelaide Druet (A)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Donglei Liu (D)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Louise Kirman (L)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Julie Lachal (J)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Kenji Namoto (K)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Douglas Bevan (D)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Rose Mo (R)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Gabriela Monnet (G)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Lionel Muller (L)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Richard Zessis (R)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Xueming Huang (X)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Loren Lindsley (L)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Treeve Currie (T)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Yu-Hsin Chiu (YH)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Cary Fridrich (C)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Peter Delgado (P)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Shuangxi Wang (S)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Micah Hollis-Symynkywicz (M)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Joerg Berghausen (J)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Eric Williams (E)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Hong Liu (H)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Guiqing Liang (G)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Hyungchul Kim (H)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Peter Hoffmann (P)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Andreas Hein (A)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Paul Ramage (P)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Allan D'Arcy (A)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Stefanie Harlfinger (S)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Martin Renatus (M)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Simon Ruedisser (S)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

David Feldman (D)

Novartis Institutes for BioMedical Research, East Hanover, New Jersey 07396, United States.

Jason Elliott (J)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

Richard Sedrani (R)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Juergen Maibaum (J)

Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.

Christopher M Adams (CM)

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.

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Classifications MeSH