title: 2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727): a potent, orally active dipeptidyl peptidase IV inhibitor without mechanism-based inactivation of CYP3A.
abstract: We report on the identification of 2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727) (7a) as a potent and orally active DPP-4 inhibitor without mechanism-based inactivation of CYP3A. Compound 7a showed good DPP-4 inhibitory activity (IC(50)=1.1 nM), excellent selectivity against related peptidases and other off-targets, good pharmacokinetic and pharmacodynamic profile, great in vivo efficacy in Zucker-fatty rat, and no safety concerns both in vitro and in vivo.
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co. Ltd, 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan. yukihiro-nishio@ds-pharma.co.jp
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Nishio
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kimura
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Sawada
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugaru
authors.forename: Masakuni
authors.initials: M
authors.lastname: Horiguchi
authors.forename: Michiko
authors.initials: M
authors.lastname: Ono
authors.forename: Yudai
authors.initials: Y
authors.lastname: Furuta
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Sakai
authors.forename: Yumi
authors.initials: Y
authors.lastname: Masui
authors.forename: Misato
authors.initials: M
authors.lastname: Otani
authors.forename: Takahiko
authors.initials: T
authors.lastname: Hashizuka
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Honda
authors.forename: Jiro
authors.initials: J
authors.lastname: Deguchi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakahira
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005951:Glucose Tolerance Test; D000882:Haplorhini; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: C569102:2-((6-(3-amino-3-methylpiperidine-1-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo(3,2-d)pyrimidine-5-yl)methyl)-4-fluorobenzonitrile; D001786:Blood Glucose; D065692:Cytochrome P-450 CYP3A Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D018819:Dipeptidyl Peptidase 4