Heteroaromatic-aminomethyl quinolones: Potent and selective iNOS inhibitors

被引：8

作者：

Duron, Sergio G. ^{[3
]}

Lindstrom, Andrew ^{[6
]}

Bonnefous, Celine ^{[1
]}

Zhang, Hui ^{[2
]}

Chen, Xiaohong ^{[2
]}

Symons, Kent T. ^{[6
]}

Sablad, Marciano ^{[4
]}

Rozenkrants, Natasha ^{[4
]}

Zhang, Yan ^{[4
]}

Wang, Li ^{[5
]}

Yazdani, Nahid ^{[6
]}

Shiau, Andrew K. ^{[8
]}

Noble, Stewart A. ^{[2
]}

Rix, Peter ^{[1
]}

Rao, Tadimeti S. ^{[4
]}

Hassig, Christian A. ^{[7
]}

Smith, Nicholas D. ^{[1
]}

机构：

[1] Aragon Pharmaceut, San Diego, CA 92121 USA

[2] Kalypsys Inc, San Diego, CA 92121 USA

[3] Afraxis, La Jolla, CA 92037 USA

[4] Johnson & Johnson PRD, San Diego, CA 92121 USA

[5] Bioquant, San Diego, CA 92121 USA

[6] Helicon, San Diego, CA 92121 USA

[7] Sanford Burnham Res Ctr, San Diego, CA 92121 USA

[8] Univ Calif San Diego, Ludwig Canc Res Ctr, La Jolla, CA 92037 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 02期

关键词：

Quinolone; Nitric oxide synthase; iNOS; nNOS; Inhibitor; SAR studies; Lipopolysaccharide challenge assay; NITRIC-OXIDE SYNTHASE; DIMERIZATION INHIBITORS; DEVELOPMENT CANDIDATE; PAIN MODELS; IDENTIFICATION; DISCOVERY; KD7332; SERIES;

D O I：

10.1016/j.bmcl.2011.11.073

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The overproduction of nitric oxide during the biological response to inflammation by the nitric oxide synthase (NOS) enzymes have been implicated in the pathology of many diseases. By removal of the amide core from uHTS-derived quinolone 4, a new series highly potent heteroaromatic-aminomethyl quinolone iNOS inhibitors 8 were identified. SAR studies led to identification of piperazine 22 and pyrimidine 32, both of which reduced plasma nitrates following oral dosing in a mouse lipopolysaccharide challenge assay. (C) 2011 Elsevier Ltd. All rights reserved.

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收藏

页码：1237 / 1241

页数：5

相关论文

共 9 条

[1] Nitric oxide synthases: structure, function and inhibition [J].

Alderton, WK ;

Cooper, CE ;

Knowles, RG .

BIOCHEMICAL JOURNAL, 2001, 357 (03) :593-615

[2] Discovery of Inducible Nitric Oxide Synthase (iNOS) Inhibitor Development Candidate KD7332, Part 1: Identification of a Novel, Potent, and Selective Series of Quinolinone iNOS Dimerization Inhibitors that are Orally Active in Rodent Pain Models [J].

Bonnefous, Celine ;

Payne, Joseph E. ;

Roppe, Jeffrey ;

Zhuang, Hui ;

Chen, Xiaohong ;

Symons, Kent T. ;

Nguyen, Phan M. ;

Sablad, Marciano ;

Rozenkrants, Natasha ;

Zhang, Yan ;

Wang, Li ;

Severance, Daniel ;

Walsh, John P. ;

Yazdani, Nahid ;

Shiau, Andrew K. ;

Noble, Stewart A. ;

Rix, Peter ;

Rao, Tadimeti S. ;

Hassig, Christian A. ;

Smith, Nicholas D. .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (09) :3047-3062

[3] Nonselective bromination-selective debromination strategy: Selective bromination of unsymmetrical ketones on singly activated carbon against doubly activated carbon [J].

Choi, HY ;

Chi, DY .

ORGANIC LETTERS, 2003, 5 (04) :411-414

[4]

Edwards RM, 1998, J PHARMACOL EXP THER, V285, P1019

[5] Antinociceptive activity of the selective iNOS inhibitor AR-C102222 in rodent models of inflammatory, neuropathic and post-operative pain [J].

LaBuda, Christopher J. ;

Koblish, Michael ;

Tuthill, Paul ;

Dolle, Roland E. ;

Little, Patrick J. .

EUROPEAN JOURNAL OF PAIN, 2006, 10 (06) :505-512

[6]

Levy Dan, 2004, Pain Pract, V4, P11, DOI 10.1111/j.1533-2500.2004.04002.x

[7] Discovery of Dual Inducible/Neuronal Nitric Oxide Synthase (iNOS/nNOS) Inhibitor Development Candidate 4-(2-Cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one (KD7332) Part 2: Identification of a Novel, Potent, and Selective Series of Benzimidazole-Quinolinone iNOS/nNOS Dimerization Inhibitors That Are Orally Active in Pain Models [J].

Payne, Joseph E. ;

Bonnefous, Celine ;

Symons, Kent T. ;

Nguyen, Phan M. ;

Sablad, Marciano ;

Rozenkrants, Natasha ;

Zhang, Yan ;

Wang, Li ;

Yazdani, Nahid ;

Shiau, Andrew K. ;

Noble, Stewart A. ;

Rix, Peter ;

Rao, Tadimeti S. ;

Hassig, Christian A. ;

Smith, Nicholas D. .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (21) :7739-7755

[8] 1,2-dihydro-4-quinazolinamines: Potent, highly selective inhibitors of inducible nitric oxide synthase which show antiinflammatory activity in vivo [J].

Tinker, AC ;

Beaton, HG ;

Boughton-Smith, N ;

Cook, TR ;

Cooper, SL ;

Fraser-Rae, L ;

Hallam, K ;

Hamley, P ;

McInally, T ;

Nicholls, DJ ;

Pimm, AD ;

Wallace, AV .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (06) :913-916

[9] Blocking NO synthesis: How, where and why? [J].

Vallance, P ;

Leiper, J .

NATURE REVIEWS DRUG DISCOVERY, 2002, 1 (12) :939-950