258331-10-1Relevant articles and documents
Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach
Lorthiois, Edwige,Roache, James,Barnes-Seeman, David,Altmann, Eva,Hassiepen, Ulrich,Turner, Gordon,Duvadie, Rohit,Hornak, Viktor,Karki, Rajeshri G.,Schiering, Nikolaus,Weihofen, Wilhelm A.,Perruccio, Francesca,Calhoun, Amy,Fazal, Tanzina,Dedic, Darija,Durand, Corinne,Dussauge, Solene,Fettis, Kamal,Tritsch, Fabien,Dentel, Celine,Druet, Adelaide,Liu, Donglei,Kirman, Louise,Lachal, Julie,Namoto, Kenji,Bevan, Douglas,Mo, Rose,Monnet, Gabriela,Muller, Lionel,Zessis, Richard,Huang, Xueming,Lindsley, Loren,Currie, Treeve,Chiu, Yu-Hsin,Fridrich, Cary,Delgado, Peter,Wang, Shuangxi,Hollis-Symynkywicz, Micah,Berghausen, Joerg,Williams, Eric,Liu, Hong,Liang, Guiqing,Kim, Hyungchul,Hoffmann, Peter,Hein, Andreas,Ramage, Paul,D'arcy, Allan,Harlfinger, Stefanie,Renatus, Martin,Ruedisser, Simon,Feldman, David,Elliott, Jason,Sedrani, Richard,Maibaum, Juergen,Adams, Christopher M.
, p. 8088 - 8113 (2020/09/23)
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.
AMINOMETHYL-BIARYL DERIVATIVES AS COMPLEMENT FACTOR D INHIBITORS AND USES THEREOF
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Page/Page column 114, (2015/02/02)
The present invention provides a compound of formula (I), a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical com
PYRROLIDINE-2-CARBONITRILE DERIVATIVES AND THEIR USE AS INHIBITORS OF DIPEPTIDYL PEPTIDASE-IV (DPP-IV)
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Page/Page column 110, (2008/06/13)
The present invention relates to compounds of formula (I), (I), which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, b-cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.
