Design, synthesis and biological evaluation of γ-lactam hydroxamate based TACE inhibitors

被引：8

作者：

Argade, Anil ^{[1
,2
]}

Bahekar, Rajesh ^{[1
]}

Desai, Jigar ^{[1
]}

Thombare, Pravin ^{[1
]}

Shah, Kiran ^{[1
]}

Gite, Sanjay ^{[1
]}

Sunder, Rajesh ^{[1
]}

Ranvir, Ramchandra ^{[1
]}

Bandyopadhyay, Debdutta ^{[1
]}

Chakrabarti, Ganes ^{[1
]}

Joharapurkar, Amit ^{[1
]}

Mahapatra, Jogeswar ^{[1
]}

Chatterjee, Abhijit ^{[1
]}

Patel, Harilal ^{[1
]}

Shaikh, Mubeen ^{[1
]}

Sairam, Kalapatapu V. V. M. ^{[1
]}

Jain, Mukul ^{[1
]}

Patel, Pankaj ^{[1
]}

机构：

[1] Zydus Res Ctr, Ahmadabad 382210, Gujarat, India

[2] Maharaja Sayajirao Univ Baroda, Fac Sci, Dept Chem, Vadodara 390002, Gujarat, India

来源：

MEDCHEMCOMM | 2011年 / 2卷 / 10期

关键词：

ALPHA CONVERTING-ENZYME; NECROSIS-FACTOR-ALPHA; SELECTIVE INHIBITORS; DISCOVERY; POTENT; METALLOPROTEINASE; DISINTEGRIN; ACIDS;

D O I：

10.1039/c0md00261e

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A new series of gamma-lactam hydroxamate based TACE inhibitors was designed mainly by introducing various substitutions at the 2nd position of the quinoline nucleus to achieve high potency and good selectivity towards TACE over matrix metalloproteases (MMPs) and ADAM-10. In ex vivo TNF-alpha inhibitory activity assays, compounds 11o and 11p were identified as the most potent compounds. The in vitro TACE inhibitory activity, selectivity over MMPs and ADAM-10 and the in vivo TNF-alpha inhibitory activities of compounds 11o and 11p were assessed and lead compound 11p was identified. Preliminary toxicity and pharmacokinetic (PK) studies were conducted for compound 11p and it showed an improved PK and clean toxicological profile compared to standard compound 1. Altogether, these results demonstrated the discovery of highly potent and selective gamma-lactam hydroxamate based TACE inhibitors which show potential for the safe and effective treatment of inflammatory diseases.

引用

页码：966 / 972

页数：7

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