Literature DB >> 24900193

The Discovery of Pyridone and Pyridazone Heterocycles as γ-Secretase Modulators.

Xianhai Huang1, Robert Aslanian1, Wei Zhou1, Xiaohong Zhu1, Jun Qin1, William Greenlee1, Zhaoning Zhu1, Lili Zhang2, Lynn Hyde2, Inhou Chu3, Mary Cohen-Williams2, Anandan Palani1.   

Abstract

A series of novel pyridazone and pyridone compounds as γ-secretase modulators were discovered. Starting from the initial lead, structure-activity relationship studies were carried out in which an internal hydrogen bond was introduced to conformationally fix the side chain, and compounds with improved in vitro Aβ42 inhibition activity and good Aβtotal/Aβ42 selectivity were quickly discovered. Compound 35 displayed very good in vitro activity and excellent selectivity with good in vivo efficacy in both CRND8 mouse and nontransgenic rat models. This compound displayed a good overall profile in terms of rat pharmacokinetics and ancillary profile. No abnormal behavior and side effects were observed in all of the studies.

Entities:  

Keywords:  Alzheimer's disease; Pyridazone; modulator; pyridone; γ-secretase

Year:  2010        PMID： 24900193      PMCID： PMC4007853          DOI： 10.1021/ml1000799

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  13 in total

1.  Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer's disease: review and current status.

Authors: 
Journal:  Expert Opin Investig Drugs       Date:  1999-10       Impact factor: 6.206

2.  Studies to investigate the in vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouse.

Authors:  Lynn A Hyde; Nansie A McHugh; Joseph Chen; Qi Zhang; Denise Manfra; Amin A Nomeir; Hubert Josien; Thomas Bara; John W Clader; Lili Zhang; Eric M Parker; Guy A Higgins
Journal:  J Pharmacol Exp Ther       Date:  2006-08-31       Impact factor: 4.030

Review 3.  Current approaches in the treatment of Alzheimer's disease.

Authors:  Reena S Shah; Hyoung-Gon Lee; Zhu Xiongwei; George Perry; Mark A Smith; Rudy J Castellani
Journal:  Biomed Pharmacother       Date:  2008-03-17       Impact factor: 6.529

Review 4.  Emerging and potential therapies for Alzheimer's disease.

Authors:  Heledd H Griffiths; Isobel J Morten; Nigel M Hooper
Journal:  Expert Opin Ther Targets       Date:  2008-06       Impact factor: 6.902

5.  Cassette-accelerated rapid rat screen: a systematic procedure for the dosing and liquid chromatography/atmospheric pressure ionization tandem mass spectrometric analysis of new chemical entities as part of new drug discovery.

Authors:  W A Korfmacher; K A Cox; K J Ng; J Veals; Y Hsieh; S Wainhaus; L Broske; D Prelusky; A Nomeir; R E White
Journal:  Rapid Commun Mass Spectrom       Date:  2001       Impact factor: 2.419

6.  Mefenamic acid shows neuroprotective effects and improves cognitive impairment in in vitro and in vivo Alzheimer's disease models.

Authors:  Yuyoung Joo; Hye-Sun Kim; Ran-Sook Woo; Cheol Hyoung Park; Ki-Young Shin; Jean-Pyo Lee; Keun-A Chang; Seonghan Kim; Yoo-Hun Suh
Journal:  Mol Pharmacol       Date:  2005-10-13       Impact factor: 4.436

Review 7.  The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.

Authors:  John Hardy; Dennis J Selkoe
Journal:  Science       Date:  2002-07-19       Impact factor: 47.728

Review 8.  Disease-modifying approach to the treatment of Alzheimer's disease: from alpha-secretase activators to gamma-secretase inhibitors and modulators.

Authors:  Francesco Panza; Vincenzo Solfrizzi; Vincenza Frisardi; Cristiano Capurso; Alessia D'Introno; Anna M Colacicco; Gianluigi Vendemiale; Antonio Capurso; Bruno P Imbimbo
Journal:  Drugs Aging       Date:  2009       Impact factor: 3.923

Review 9.  Advances in gamma-secretase modulation.

Authors:  Dmitri Pissarnitski
Journal:  Curr Opin Drug Discov Devel       Date:  2007-07

10.  Progress in Alzheimer's disease drug discovery: an update.

Authors:  Michael Williams
Journal:  Curr Opin Investig Drugs       Date:  2009-01
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  6 in total

1.  Synthesis and SAR Studies of Fused Oxadiazines as γ-Secretase Modulators for Treatment of Alzheimer's Disease.

Authors:  Xianhai Huang; Wei Zhou; Xiaoxiang Liu; Hongmei Li; George Sun; Mihirbaran Mandal; Monica Vicarel; Xiaohong Zhu; Chad Bennett; Troy McCraken; Dmitri Pissarnitski; Zhiqiang Zhao; David Cole; Gioconda Gallo; Zhaoning Zhu; Anandan Palani; Robert Aslanian; John Clader; Michael Czarniecki; William Greenlee; Duane Burnett; Mary Cohen-Williams; Lynn Hyde; Lixin Song; Lili Zhang; Inhou Chu; Alexei Buevich
Journal:  ACS Med Chem Lett       Date:  2012-09-04       Impact factor: 4.345

2.  Discovery of a Potent Pyrazolopyridine Series of γ-Secretase Modulators.

Authors:  Jun Qin; Wei Zhou; Xianhai Huang; Pawan Dhondi; Anandan Palani; Robert Aslanian; Zhaoning Zhu; William Greenlee; Mary Cohen-Williams; Nicholas Jones; Lynn Hyde; Lili Zhang
Journal:  ACS Med Chem Lett       Date:  2011-03-29       Impact factor: 4.345

Review 3.  Development and mechanism of γ-secretase modulators for Alzheimer's disease.

Authors:  Christina J Crump; Douglas S Johnson; Yue-Ming Li
Journal:  Biochemistry       Date:  2013-05-02       Impact factor: 3.162

4.  Discovery of a Tetrahydrobenzisoxazole Series of γ-Secretase Modulators.

Authors:  Zhiqiang Zhao; Dmitri A Pissarnitski; Xianhai Huang; Anandan Palani; Zhaoning Zhu; William J Greenlee; Lynn A Hyde; Lixin Song; Giuseppe Terracina; Lili Zhang; Eric M Parker
Journal:  ACS Med Chem Lett       Date:  2017-09-19       Impact factor: 4.345

5.  Completely N1-selective palladium-catalyzed arylation of unsymmetric imidazoles: application to the synthesis of nilotinib.

Authors:  Satoshi Ueda; Mingjuan Su; Stephen L Buchwald
Journal:  J Am Chem Soc       Date:  2011-12-14       Impact factor: 15.419

6.  Evaluation of Virtual Screening Strategies for the Identification of γ-Secretase Inhibitors and Modulators.

Authors:  Alicia Ioppolo; Melissa Eccles; David Groth; Giuseppe Verdile; Mark Agostino
Journal:  Molecules       Date:  2021-12-28       Impact factor: 4.411
  6 in total

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