title: (R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: design, synthesis, biological evaluation, and molecular modeling.
abstract: A series of (R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives was designed, synthesized, and evaluated as novel inhibitors of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes. Most of the synthesized compounds demonstrated good inhibition activities against DPP-4. Among these, compounds 3e, 4c, 4l, and 4n exhibited prominent inhibition activities against DPP-4, with IC50s of 0.07, 0.07, 0.14, and 0.17μM, respectively. The possible binding modes of compounds 3e and 4n with dipeptidyl peptidase-4 were also explored by molecular docking simulation. These potent DPP-4 inhibitors were optimized for the absorption, distribution, metabolism, and excretion (ADME) properties, and compound 4n displayed an attractive pharmacokinetic profile (F=96.3%, t1/2=10.5h).
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Sinan
authors.initials: S
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Mingbo
authors.initials: M
authors.lastname: Su
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Zeng
authors.initials: Z
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Xun
authors.initials: X
authors.lastname: Ji
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, People's Republic of China.
authors.forename: Jingya
authors.initials: J
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, People's Republic of China. Electronic address: jli@simm.ac.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, People's Republic of China. Electronic address: hliu@simm.ac.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; C000601699:N-((1-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)octahydro-1H-indol-2-yl)methyl)-1,1,1-trifluoromethanesulfonamide; D011994:Recombinant Proteins; D013449:Sulfonamides; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: Binding mode; DPP-4; Inhibitor; Oral bioavailability; Type 2 diabetes