Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding

被引：44

作者：

Cox, Christopher D. ^{[1
]}

McGaughey, Georgia B. ^{[1
]}

Bogusky, Michael J. ^{[1
]}

Whitman, David B. ^{[1
]}

Ball, Richard G. ^{[2
]}

Winrow, Christopher J. ^{[3
]}

Renger, John J. ^{[3
]}

Coleman, Paul J. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Pharmaceut Res, Rahway, NJ 07065 USA

[3] Merck Res Labs, Dept Depress & Circadian Disorders, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 11期

关键词：

Orexin receptor antagonist; Diazepane; Pi-stacking; Macrocyclicization; PI-STACKING INTERACTIONS; DESIGN; STATE;

D O I：

10.1016/j.bmcl.2009.04.026

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

NMR spectroscopy, X-ray crystallography, and molecular modeling studies indicate that N,N-disubstituted-1,4-diazepane orexin receptor antagonists exist in an unexpected low-energy conformation that is characterized by an intramolecular pi-stacking interaction and a twist-boat ring conformation. Synthesis and evaluation of a macrocycle that enforces a similar conformation suggest that this geometry mimics the bioactive conformation. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：2997 / 3001

页数：5

共 28 条

[1] Structural insights into the design of nonpeptidic isothiazolidinone-containing inhibitors of protein-tyrosine phosphatase 1B [J].

Ala, Paul J. ;

Gonneville, Lucie ;

Hillman, Milton ;

Becker-Pasha, Mary ;

Yue, Eddy W. ;

Douty, Brent ;

Wayland, Brian ;

Polam, Padmaja ;

Crawley, Matthew L. ;

McLaughlin, Erin ;

Sparks, Richard B. ;

Glass, Brian ;

Takvorian, Amy ;

Combs, Andrew P. ;

Burn, Timothy C. ;

Hollis, Gregory F. ;

Wynn, Richard .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (49) :38013-38021

[2] Copper-diamine-catalyzed N-arylation of pyrroles, pyrazoles, indazoles, imidazoles, and triazoles [J].

Antilla, JC ;

Baskin, JM ;

Barder, TE ;

Buchwald, SL .

JOURNAL OF ORGANIC CHEMISTRY, 2004, 69 (17) :5578-5587

[3]

Bingham MJ, 2006, CURR OPIN DRUG DISC, V9, P551

[4] Orexin Receptor Antagonism: A New Principle in Neuroscience [J].

Boss, Christoph ;

Brisbare-Roch, Catherine ;

Jenck, Francois ;

Aissaoui, Hamed ;

Koberstein, Ralf ;

Sifferlen, Thierry ;

Weller, Thomas .

CHIMIA, 2008, 62 (12) :974-979

[5] Biomedical Application of Orexin/Hypocretin Receptor Ligands in Neuroscience [J].

Boss, Christoph ;

Brisbare-Roch, Catherine ;

Jenck, Francois .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (04) :891-903

[6]

BRESLIN MJ, 2008, 236 ACS NAT M PHIL P

[7] AROMATIC-AROMATIC INTERACTION - A MECHANISM OF PROTEIN-STRUCTURE STABILIZATION [J].

BURLEY, SK ;

PETSKO, GA .

SCIENCE, 1985, 229 (4708) :23-28

[8]

COX PJ, 2007, Patent No. 2007126935

[9] FROM MOLECULAR TO CRYSTAL-STRUCTURE - POLYNUCLEAR AROMATIC-HYDROCARBONS [J].

DESIRAJU, GR ;

GAVEZZOTTI, A .

JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1989, (10) :621-623

[10]

Eliel E. L., 1994, STEREOCHEMISTRY ORGA

← 1 2 3 →