Synthesis, Stereochemical Separation, and Biological Evaluation of Selective Inhibitors of Human MAO-B: 1-(4-Arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazines

被引：39

作者：

Chimenti, Franco ^{[1
]}

Secci, Daniela ^{[1
]}

Bolasco, Adriana ^{[1
]}

Chimenti, Paola ^{[1
]}

Granese, Arianna ^{[1
]}

Carradori, Simone ^{[1
]}

Yanez, Matilde ^{[2
,3
]}

Orallo, Francisco ^{[2
,3
]}

Sanna, M. Luisa ^{[4
]}

Gallinella, Bruno ^{[4
]}

Cirilli, Roberto ^{[4
]}

机构：

[1] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy

[2] Univ Santiago de Compostela, Fac Farm, Dept Farmacol, E-15782 Santiago De Compostela, La Coruna, Spain

[3] Univ Santiago de Compostela, Fac Farm, Inst Farm Ind, E-15782 Santiago De Compostela, La Coruna, Spain

[4] Ist Super Sanita, Dipartimento Farmaco, I-00161 Rome, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 17期

关键词：

MONOAMINE-OXIDASE-B; PARKINSONS-DISEASE; 2-THIAZOLYLHYDRAZONE DERIVATIVES; RASAGILINE; GENE;

D O I：

10.1021/jm100120s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Novel 1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazine derivatives have been investigated for their ability to inhibit selectively the activity of the human B isoform of monoamine oxidase. These compounds were obtained as racemates and (R)-enantiomers by a stereoconservative synthetic pattern in high yield and enantiomeric excess. The (S)-enantiomers of the most active derivatives have been separated by enantioselective HPLC. All compounds showed selective activity against hMAO-B with IC(50) ranging between 21.90 and 0.018 mu M.

引用

页码：6516 / 6520

页数：5

共 30 条

[11] A Novel Histone Acetyltransferase Inhibitor Modulating Gcn5 Network: Cyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl)hydrazone [J].

Chimenti, Franco ;

Bizzarri, Bruna ;

Maccioni, Elias ;

Secci, Daniela ;

Bolasco, Adriana ;

Chimenti, Paola ;

Fioravanti, Rossella ;

Granese, Arianna ;

Carradori, Simone ;

Tosi, Federica ;

Ballario, Paola ;

Vernarecci, Stefano ;

Filetici, Patrizia .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (02) :530-536

[12] High-performance liquid chromatographic separation of enantiomers and diastereomers of 2-methylcyclohexanone thiosemicarbazone, and determination of absolute configuration and configurational stability [J].

Cirilli, R. ;

Feffetti, R. ;

La Torre, F. ;

Secci, D. ;

Bolasco, A. ;

Carradori, S. ;

Pierini, A. .

JOURNAL OF CHROMATOGRAPHY A, 2007, 1172 (02) :160-169

[13]

DAPRADA M, 1990, J NEUR TR S, V29, P279

[14] Drug treatment of Parkinson's disease - Time for phase II [J].

Drukarch, B ;

van Muiswinkel, FL .

BIOCHEMICAL PHARMACOLOGY, 2000, 59 (09) :1023-1031

[15] New insights into the structures and functions of human monoamine oxidases A and B [J].

Edmondson, D. E. ;

DeColibus, L. ;

Binda, C. ;

Li, M. ;

Mattevi, A. .

JOURNAL OF NEURAL TRANSMISSION, 2007, 114 (06) :703-705

[16] Molecular and Mechanistic Properties of the Membrane-Bound Mitochondrial Monoamine Oxidases [J].

Edmondson, Dale E. ;

Binda, Claudia ;

Wang, Jin ;

Upadhyay, Anup K. ;

Mattevi, Andrea .

BIOCHEMISTRY, 2009, 48 (20) :4220-4230

[17] Structure and mechanism of monoamine oxidase [J].

Edmondson, DE ;

Mattevi, A ;

Binda, C ;

Li, M ;

Hubálek, F .

CURRENT MEDICINAL CHEMISTRY, 2004, 11 (15) :1983-1993

[18]

Guay David R P, 2006, Am J Geriatr Pharmacother, V4, P330, DOI 10.1016/j.amjopharm.2006.12.001

[19] Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase B by specific reversible inhibitors [J].

Hubálek, F ;

Binda, C ;

Khalil, A ;

Li, M ;

Mattevi, A ;

Castagnoli, N ;

Edmondson, DE .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (16) :15761-15766

[20] Functional role of the "aromatic cage" in human monoamine oxidase B: Structures and catalytic properties of Tyr435 mutant proteins [J].

Li, M ;

Binda, C ;

Mattevi, A ;

Edmondson, DE .

BIOCHEMISTRY, 2006, 45 (15) :4775-4784

← 1 2 3 →