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.
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.
Yoshikawa
Kenji
K
R&D Division, Daiichi Sankyo Co, Ltd, Tokyo 134-8630, Japan. yoshikawa.kenji.t6@daiichisankyo.co.jp
Yokomizo
Aki
A
Naito
Hiroyuki
H
Haginoya
Noriyasu
N
Kobayashi
Shozo
S
Yoshino
Toshiharu
T
Nagata
Tsutomu
T
Mochizuki
Akiyoshi
A
Osanai
Ken
K
Watanabe
Kengo
K
Kanno
Hideyuki
H
Ohta
Toshiharu
T
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
D000925:Anticoagulants; D003514:Cyclohexylamines; D010980:Platelet Membrane Glycoproteins; C045069:factor X receptors; D000990:Antithrombin III; C030435:1,2-cyclohexanediamine