The Discovery of Pyridone and Pyridazone Heterocycles As γ-Secretase Modulators

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Jun 6

PMID 24900193

Citations 6

Authors

Xianhai Huang

Robert Aslanian

Wei Zhou

Xiaohong Zhu

Jun Qin

William Greenlee

Zhaoning Zhu

Lili Zhang

Lynn Hyde

Inhou Chu

Mary Cohen-Williams

Anandan Palani

Affiliations

Soon will be listed here.

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.

Citing Articles

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

Ioppolo A, Eccles M, Groth D, Verdile G, Agostino M Molecules. 2022; 27(1).

PMID: 35011410 PMC: 8746326. DOI: 10.3390/molecules27010176.

Discovery of a Tetrahydrobenzisoxazole Series of γ-Secretase Modulators.

Zhao Z, Pissarnitski D, Huang X, Palani A, Zhu Z, Greenlee W ACS Med Chem Lett. 2017; 8(10):1002-1006.

PMID: 29057041 PMC: 5641957. DOI: 10.1021/acsmedchemlett.7b00178.

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

Huang X, Zhou W, Liu X, Li H, Sun G, Mandal M ACS Med Chem Lett. 2014; 3(11):931-5.

PMID: 24900409 PMC: 4025817. DOI: 10.1021/ml300209g.

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

Qin J, Zhou W, Huang X, Dhondi P, Palani A, Aslanian R ACS Med Chem Lett. 2014; 2(6):471-6.

PMID: 24900332 PMC: 4018171. DOI: 10.1021/ml2000438.

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

Crump C, Johnson D, Li Y Biochemistry. 2013; 52(19):3197-216.

PMID: 23614767 PMC: 3796170. DOI: 10.1021/bi400377p.

References

Panza F, Solfrizzi V, Frisardi V, Capurso C, DIntrono A, Colacicco A . Disease-modifying approach to the treatment of Alzheimer's disease: from alpha-secretase activators to gamma-secretase inhibitors and modulators. Drugs Aging. 2009; 26(7):537-55. DOI: 10.2165/11315770-000000000-00000. View

Williams M . Progress in Alzheimer's disease drug discovery: an update. Curr Opin Investig Drugs. 2009; 10(1):23-34. View

Griffiths H, Morten I, Hooper N . Emerging and potential therapies for Alzheimer's disease. Expert Opin Ther Targets. 2008; 12(6):693-704. DOI: 10.1517/14728222.12.6.693. View

Hardy J, Selkoe D . The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002; 297(5580):353-6. DOI: 10.1126/science.1072994. View

Korfmacher W, Cox K, Ng K, Veals J, Hsieh Y, Wainhaus S . 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. Rapid Commun Mass Spectrom. 2001; 15(5):335-40. DOI: 10.1002/rcm.235. View

Rajendran L, Schneider A, Schlechtingen G, Weidlich S, Ries J, Braxmeier T . Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting. Science. 2008; 320(5875):520-3. DOI: 10.1126/science.1156609. View

Shah R, Lee H, Xiongwei Z, Perry G, Smith M, Castellani R . Current approaches in the treatment of Alzheimer's disease. Biomed Pharmacother. 2008; 62(4):199-207. DOI: 10.1016/j.biopha.2008.02.005. View

Joo Y, Kim H, Woo R, Park C, Shin K, Lee J . Mefenamic acid shows neuroprotective effects and improves cognitive impairment in in vitro and in vivo Alzheimer's disease models. Mol Pharmacol. 2005; 69(1):76-84. DOI: 10.1124/mol.105.015206. View

Kokotos G, Noula C . Selective One-Pot Conversion of Carboxylic Acids into Alcohols. J Org Chem. 1996; 61(20):6994-6996. DOI: 10.1021/jo9520699. View

10.

GOTTWALD , Rozanski . Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer's disease: review and current status. Expert Opin Investig Drugs. 2001; 8(10):1673-1682. DOI: 10.1517/13543784.8.10.1673. View

11.

Davis K . NSAID and Alzheimer's disease; possible answers and new questions. Mol Psychiatry. 2002; 7(9):925-6. DOI: 10.1038/sj.mp.4001123. View

12.

Hyde L, McHugh N, Chen J, Zhang Q, Manfra D, Nomeir A . 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. J Pharmacol Exp Ther. 2006; 319(3):1133-43. DOI: 10.1124/jpet.106.111716. View

13.

Pissarnitski D . Advances in gamma-secretase modulation. Curr Opin Drug Discov Devel. 2007; 10(4):392-402. View