title: Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part I: exploration of 5-6 fused rings as alternative S1 moieties.
abstract: A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.
authors.affiliation: R&D Division, Daiichi Sankyo Co, Ltd, Tokyo 134-8630, Japan. yoshikawa.kenji.t6@daiichisankyo.co.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Aki
authors.initials: A
authors.lastname: Yokomizo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Naito
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Haginoya
authors.forename: Shozo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yoshino
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nagata
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Mochizuki
authors.forename: Ken
authors.initials: K
authors.lastname: Osanai
authors.forename: Kengo
authors.initials: K
authors.lastname: Watanabe
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kanno
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000627:therapeutic use*; D000990:Antithrombin III / Q000627:therapeutic use*; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D003514:Cyclohexylamines / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007408:Intestinal Absorption / Q000187:drug effects; D007700:Kinetics; D015394:Molecular Structure; D010980:Platelet Membrane Glycoproteins; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000925:Anticoagulants; D003514:Cyclohexylamines; D010980:Platelet Membrane Glycoproteins; C045069:factor X receptors; D000990:Antithrombin III; C030435:1,2-cyclohexanediamine