title: Anagliptin, a potent dipeptidyl peptidase IV inhibitor: its single-crystal structure and enzyme interactions.
abstract: The single-crystal structure of anagliptin, N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide, was determined. Two independent molecules were held together by intermolecular hydrogen bonds, and the absolute configuration of the 2-cyanopyrrolidine ring delivered from l-prolinamide was confirmed to be S. The interactions of anagliptin with DPP-4 were clarified by the co-crystal structure solved at 2.85 Å resolution. Based on the structure determined by X-ray crystallography, the potency and selectivity of anagliptin were discussed, and an SAR study using anagliptin derivatives was performed.
authors.affiliation: a Mie Research Park, Sanwa Kagaku Kenkyusho Co., Ltd. , Mie , Japan .
authors.forename: Yukihisa S
authors.initials: YS
authors.lastname: Watanabe
authors.affiliation: a Mie Research Park, Sanwa Kagaku Kenkyusho Co., Ltd. , Mie , Japan .
authors.forename: Yoshika
authors.initials: Y
authors.lastname: Yasuda
authors.affiliation: b Yokohama Laboratory , Mitsubishi Chemical Group Science and Technology Research Center Inc. , Yokohama , Japan .
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: c Sosho, Inc. , Osaka , Japan , and.
authors.forename: Shino
authors.initials: S
authors.lastname: Okada
authors.affiliation: c Sosho, Inc. , Osaka , Japan , and.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Motoyama
authors.affiliation: d Sysmex Corporation , Kobe , Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: a Mie Research Park, Sanwa Kagaku Kenkyusho Co., Ltd. , Mie , Japan .
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Oka
mesh_terms: D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011743:Pyrimidines; D018819:Dipeptidyl Peptidase 4; C583175:anagliptin
keywords: Co-crystal structure; DPP-4 inhibitor; X-ray crystallography; transition-state interaction; type 2 diabetes