Design and synthesis of DPP-IV inhibitors lacking the electrophilic nitrile group

Takashi Kondo; Takahiro Nekado; Isamu Sugimoto; Kenya Ochi; Shigeyuki Takai; Atsushi Kinoshita; Akira Hatayama; Susumu Yamamoto; Katsuya Kishikawa; Hisao Nakai; Masaaki Toda

doi:10.1016/j.bmc.2007.11.031

Design and synthesis of DPP-IV inhibitors lacking the electrophilic nitrile group

Takashi Kondo, Takahiro Nekado, Isamu Sugimoto, Kenya Ochi, Shigeyuki Takai, Atsushi Kinoshita, Akira Hatayama, Susumu Yamamoto, Katsuya Kishikawa, Hisao Nakai, Masaaki Toda

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

Abstract

A series of (4β-substituted)-l-prolylpyrrolidine analogs lacking the electrophilic nitrile function were synthesized and their dipeptidyl peptidase IV (DPP-IV) inhibitory activity and duration of ex vivo activity were evaluated. Structural optimization of a N-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine analog 8, which was found by high-speed analog synthesis, was carried out to improve the potency and duration of action. A representative compound 26 was evaluated to assess its effect on the plasma glucose level after the oGTT (oral glucose tolerance test) in normal rats. Structure-activity relationships (SAR) are also presented.

Original language	English
Pages (from-to)	1613-1631
Number of pages	19
Journal	Bioorganic and Medicinal Chemistry
Volume	16
Issue number	4
DOIs	https://doi.org/10.1016/j.bmc.2007.11.031
Publication status	Published - 2008 Feb 15
Externally published	Yes

Keywords

(4β-Substituted)-l-prolylpyrrolidine
1,2,4-Thiadiazol-5-yl-piperazine
DPP-IV inhibitor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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Design and synthesis of DPP-IV inhibitors lacking the electrophilic nitrile group. / Kondo, Takashi; Nekado, Takahiro; Sugimoto, Isamu; Ochi, Kenya; Takai, Shigeyuki; Kinoshita, Atsushi; Hatayama, Akira; Yamamoto, Susumu; Kishikawa, Katsuya; Nakai, Hisao; Toda, Masaaki.

In: Bioorganic and Medicinal Chemistry, Vol. 16, No. 4, 15.02.2008, p. 1613-1631.

Research output: Contribution to journal › Article › peer-review

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AU - Kinoshita, Atsushi

AU - Hatayama, Akira

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AU - Toda, Masaaki

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