Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators

Weiwei Mao; Mengmeng Ning; Zhiqing Liu; Qingzhang Zhu; Ying Leng; Ao Zhang

doi:10.1016/j.bmc.2012.03.008

Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators

Weiwei Mao, Mengmeng Ning, Zhiqing Liu, Qingzhang Zhu, Ying Leng, Ao Zhang

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

46 Scopus citations

Abstract

A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC ₅₀ values of 28.3 and 44.8 nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds.

Original language	English (US)
Pages (from-to)	2982-2991
Number of pages	10
Journal	Bioorganic and Medicinal Chemistry
Volume	20
Issue number	9
DOIs	https://doi.org/10.1016/j.bmc.2012.03.008
State	Published - May 1 2012
Externally published	Yes

Keywords

Aminothiazole
Benzamide derivatives
Glucokinase activator
Privileged-fragment-merging
Type 2 diabetes (T2D)

ASJC Scopus subject areas

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

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10.1016/j.bmc.2012.03.008

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title = "Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators",

abstract = "A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC 50 values of 28.3 and 44.8 nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds.",

keywords = "Aminothiazole, Benzamide derivatives, Glucokinase activator, Privileged-fragment-merging, Type 2 diabetes (T2D)",

author = "Weiwei Mao and Mengmeng Ning and Zhiqing Liu and Qingzhang Zhu and Ying Leng and Ao Zhang",

note = "Funding Information: This work was supported by Grants from Chinese National Science Foundation (81125021, 81072528), National Basic Research Program of China (973 Program, 2009CB522300), National Science & Technology Major Project on {\textquoteleft}Key New Drug Creation and Manufacturing Program{\textquoteright}, China (Numbers: 2012ZX09103-101-035). Support of Shanghai postdoctoral research funding program (Numbers: 11R21417900) is also appreciated.",

year = "2012",

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doi = "10.1016/j.bmc.2012.03.008",

language = "English (US)",

volume = "20",

pages = "2982--2991",

journal = "Bioorganic and Medicinal Chemistry",

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T1 - Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators

AU - Mao, Weiwei

AU - Ning, Mengmeng

AU - Liu, Zhiqing

AU - Zhu, Qingzhang

AU - Leng, Ying

AU - Zhang, Ao

N1 - Funding Information: This work was supported by Grants from Chinese National Science Foundation (81125021, 81072528), National Basic Research Program of China (973 Program, 2009CB522300), National Science & Technology Major Project on ‘Key New Drug Creation and Manufacturing Program’, China (Numbers: 2012ZX09103-101-035). Support of Shanghai postdoctoral research funding program (Numbers: 11R21417900) is also appreciated.

PY - 2012/5/1

Y1 - 2012/5/1

N2 - A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC 50 values of 28.3 and 44.8 nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds.

AB - A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC 50 values of 28.3 and 44.8 nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds.

KW - Aminothiazole

KW - Benzamide derivatives

KW - Glucokinase activator

KW - Privileged-fragment-merging

KW - Type 2 diabetes (T2D)

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JO - Bioorganic and Medicinal Chemistry

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IS - 9

ER -

Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators

Abstract

Keywords

ASJC Scopus subject areas

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