Use of Structure-Based Design to Discover a Potent, Selective, In Vivo Active Phosphodiesterase 10A Inhibitor Lead Series for the Treatment of Schizophrenia

被引：49

作者：

Helal, Christopher J. ^{[1
]}

Kang, Zhijun ^{[1
]}

Hou, Xinjun ^{[1
]}

Pandit, Jayvardhan ^{[1
]}

Chappie, Thomas A. ^{[1
]}

Humphrey, John M. ^{[1
]}

Marr, Eric S. ^{[1
]}

Fennell, Kimberly F. ^{[1
]}

Chenard, Lois K. ^{[1
]}

Fox, Carol ^{[1
]}

Schmidt, Christopher J. ^{[1
]}

Williams, Robert D. ^{[1
]}

Chapin, Douglas S. ^{[1
]}

Siuciak, Judith ^{[1
]}

Lebel, Lorraine ^{[1
]}

Menniti, Frank ^{[1
]}

Cianfrogna, Julia ^{[1
]}

Fonseca, Kari R. ^{[1
]}

Nelson, Frederick R. ^{[1
]}

O'Connor, Rebecca ^{[1
]}

MacDougall, Mary ^{[1
]}

McDowell, Laura ^{[1
]}

Liras, Spiros ^{[1
]}

机构：

[1] Pfizer Worldwide Res & Dev, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 13期

关键词：

CENTRAL-NERVOUS-SYSTEM; P-GLYCOPROTEIN; III INHIBITOR; DRUGS; GENERATION; PDE10A; LIGAND; BRAIN;

D O I：

10.1021/jm2001508

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.

引用

页码：4536 / 4547

页数：12

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