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

Yukihiro Nishio; Hidenori Kimura; Naoyuki Sawada; Eiji Sugaru; Masakuni Horiguchi; Michiko Ono; Yudai Furuta; Mutsuko Sakai; Yumi Masui; Misato Otani; Takahiko Hashizuka; Yayoi Honda; Jiro Deguchi; Tsutomu Nakagawa; Hiroyuki Nakahira

doi:10.1016/j.bmc.2011.07.042

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

Bioorg Med Chem. 2011 Sep 15;19(18):5490-9. doi: 10.1016/j.bmc.2011.07.042. Epub 2011 Aug 4.

Authors

Yukihiro Nishio¹, Hidenori Kimura, Naoyuki Sawada, Eiji Sugaru, Masakuni Horiguchi, Michiko Ono, Yudai Furuta, Mutsuko Sakai, Yumi Masui, Misato Otani, Takahiko Hashizuka, Yayoi Honda, Jiro Deguchi, Tsutomu Nakagawa, Hiroyuki Nakahira

Affiliation

¹ 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

PMID: 21865048
DOI: 10.1016/j.bmc.2011.07.042

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.

MeSH terms

Animals
Blood Glucose / metabolism
Cytochrome P-450 CYP3A / metabolism
Cytochrome P-450 CYP3A Inhibitors*
Dipeptidyl Peptidase 4 / metabolism
Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis
Dipeptidyl-Peptidase IV Inhibitors / chemistry
Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
Dogs
Dose-Response Relationship, Drug
Glucose Tolerance Test
Haplorhini
Humans
Male
Molecular Conformation
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Rats
Rats, Zucker
Stereoisomerism
Structure-Activity Relationship
Time Factors

Substances

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
Blood Glucose
Cytochrome P-450 CYP3A Inhibitors
Dipeptidyl-Peptidase IV Inhibitors
Pyrazoles
Pyrimidines
CYP3A protein, human
Cytochrome P-450 CYP3A
Dipeptidyl Peptidase 4