title: Lead optimization of [(S)-gamma-(arylamino)prolyl]thiazolidine focused on gamma-substituent: Indoline compounds as potent DPP-IV inhibitors.
abstract: Dipeptidyl peptidase IV (DPP-IV) inhibitors are looked to as a potential new antidiabetic agent class. A series of [(S)-gamma-(arylamino)prolyl]thiazolidine compounds in which the electrophilic nitrile is removed are chemically stable DPP-IV inhibitors. To discover a structure for the gamma-substituent of the proline moiety more suitable for interacting with the S(2) pocket of DPP-IV, optimization focused on the gamma-substituent was carried out. The indoline compound 22e showed a DPP-IV-inhibitory activity 100-fold more potent than that of the prolylthiazolidine 10 and comparable to that of NVP-DPP728. It also displayed improved inhibitory selectivity for DPP-IV over DPP8 and DPP9 compared to compound 10. Indoline compounds such as 22e have a rigid conformation with double restriction of the aromatic moiety by proline and indoline structures to promote interaction with the binding site in the S(2) pocket of DPP-IV. The double restriction effect provides a potent inhibitory activity which compensates for the decrease in activity caused by removing the electrophilic nitrile.
authors.affiliation: Chemistry Laboratory, Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakashita
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Akahoshi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yoshida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitajima
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ishii
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takashina
authors.forename: Reiko
authors.initials: R
authors.lastname: Tsutsumiuchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ono
mesh_terms: D000818:Animals; D001665:Binding Sites; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D006801:Humans; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D007202:Indicators and Reagents; D011480:Protease Inhibitors; D053778:Thiazolidines; D018819:Dipeptidyl Peptidase 4