Discovery of a Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitor for the Potential Treatment of Schizophrenia

被引：39

作者：

Manuel Bartolome-Nebreda, Jose ^{[1
]}

Delgado, Francisca ^{[1
]}

Luz Martin-Martin, Maria ^{[1
]}

Martinez-Viturro, Carlos M. ^{[1
]}

Pastor, Joaquin ^{[1
]}

Min Tong, Han ^{[1
]}

Iturrino, Laura ^{[2
]}

Macdonald, Gregor J. ^{[3
]}

Sanderson, Wendy ^{[4
]}

Megens, Anton ^{[5
]}

Langlois, Xavier ^{[5
]}

Somers, Marijke ^{[6
]}

Vanhoof, Greet ^{[7
]}

Conde-Ceide, Susana ^{[1
]}

机构：

[1] Janssen Res & Dev, Neurosci Med Chem, Toledo 45007, Spain

[2] Janssen Res & Dev, Discovery Sci Analyt Sci, Toledo 45007, Spain

[3] Janssen Res & Dev, Neurosci Med Chem, B-2340 Beerse, Belgium

[4] Janssen Res & Dev, Discovery Sci Mol Informat, B-2340 Beerse, Belgium

[5] Janssen Res & Dev, Neurosci Biol, B-2340 Beerse, Belgium

[6] Janssen Res & Dev, Discovery Sci ADME Tox, B-2340 Beerse, Belgium

[7] Janssen Res & Dev, Discovery Sci Translat Sci, B-2340 Beerse, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 10期

关键词：

PDE10A INHIBITORS; IMMUNOHISTOCHEMICAL LOCALIZATION; SUBSTRATE SELECTIVITY; HUNTINGTONS-DISEASE; PYRAZOLOQUINOLINES; RECEPTOR; BRAIN; DRUGS;

D O I：

10.1021/jm500073h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure activity and structure property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.

引用

页码：4196 / 4212

页数：17

共 45 条

[1]

[Anonymous], MOL OP ENV MOE V2012

[2]

Barlolome-Nebreda J. M., 2011, Janssen Pharmacculica N V, Patent No. [WO/2011/110545A1, 2011110545, WO2011110545A1]

[3] Discovery of imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors [J].

Belanger, David B. ;

Curran, Patrick J. ;

Hruza, Alan ;

Voigt, Johannes ;

Meng, Zhaoyang ;

Mandal, Amit K. ;

Siddiqui, M. Arshad ;

Basso, Andrea D. ;

Gray, Kimberly .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (17) :5170-5174

[4] Cyclic nucleotide phosphodiesterases: Molecular regulation to clinical use [J].

Bender, Andrew T. ;

Beavo, Joseph A. .

PHARMACOLOGICAL REVIEWS, 2006, 58 (03) :488-520

[5] PDE Inhibition and cognition enhancement [J].

Blokland, Arjan ;

Menniti, Frank S. ;

Prickaerts, Jos .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2012, 22 (04) :349-354

[6] Structural basis for the activity of drugs that inhibit phosphodiesterases [J].

Card, GL ;

England, BP ;

Suzuki, Y ;

Fong, D ;

Powell, B ;

Lee, B ;

Luu, C ;

Tabrizizad, M ;

Gillette, S ;

Ibrahim, PN ;

Artis, DR ;

Bollag, G ;

Milburn, MV ;

Kim, SH ;

Schlessinger, J ;

Zhang, KYJ .

STRUCTURE, 2004, 12 (12) :2233-2247

[7] Preclinical Evaluation of 18F-JNJ41510417 as a Radioligand for PET Imaging of Phosphodiesterase-10A in the Brain [J].

Celen, Sofie ;

Koole, Michel ;

De Angelis, Meri ;

Sannen, Ivan ;

Chitneni, Satish K. ;

Alcazar, Jesus ;

Dedeurwaerdere, Stefanie ;

Moechars, Dieder ;

Schmidt, Mark ;

Verbruggen, Alfons ;

Langlois, Xavier ;

Van Laere, Koen ;

Andres, Jose Ignacio ;

Bormans, Guy .

JOURNAL OF NUCLEAR MEDICINE, 2010, 51 (10) :1584-1591

[8] Discovery of a series of 6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors [J].

Chappie, Thomas A. ;

Humphrey, John M. ;

Allen, Martin P. ;

Estep, Kimberly G. ;

Fox, Carol B. ;

Lebel, Lorraine A. ;

Liras, Spiros ;

Marr, Eric S. ;

Menniti, Frank S. ;

Pandit, Jayvardhan ;

Schmidt, Christopher J. ;

Tu, Meihua ;

Williams, Robert D. ;

Yang, Feng V. .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (02) :182-185

[9] Current Landscape of Phosphodiesterase 10A (PDE10A) Inhibition [J].

Chappie, Thomas A. ;

Helal, Christopher J. ;

Hou, Xinjun .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (17) :7299-7331

[10] Immunohistochemical localization of phosphodiesterase 10A in multiple mammalian species [J].

Coskran, Timothy M. ;

Morton, Daniel ;

Menniti, Frank S. ;

Adamowicz, Wendy O. ;

Kleiman, Robin J. ;

Ryan, Anne M. ;

Strick, Christine A. ;

Schmidt, Christopher J. ;

Stephenson, Diane T. .

JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY, 2006, 54 (11) :1205-1213

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