title: Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors.
abstract: Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor.
authors.affiliation: Discovery Chemistry and Cardiovascular Biology, Research and Development, Bristol-Myers Squibb Company , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08543, United States.
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Cailan
authors.initials: C
authors.lastname: Wang
authors.forename: Francis
authors.initials: F
authors.lastname: Woerner
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Smallheer
authors.forename: Frank A
authors.initials: FA
authors.lastname: Barbera
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Bozarth
authors.forename: Randi L
authors.initials: RL
authors.lastname: Brown
authors.forename: Mark R
authors.initials: MR
authors.lastname: Harpel
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Paul E
authors.initials: PE
authors.lastname: Morin
authors.forename: Tara
authors.initials: T
authors.lastname: Peterson
authors.forename: Vidhyashankar
authors.initials: V
authors.lastname: Ramamurthy
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.forename: Carol A
authors.initials: CA
authors.lastname: Watson
authors.forename: Anzhi
authors.initials: A
authors.lastname: Wei
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Dietmar
authors.initials: D
authors.lastname: Seiffert
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
mesh_terms: D000818:Animals; D001760:Bleeding Time; D018360:Crystallography, X-Ray; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011804:Quinolines