Discovery of Clinical Candidate 1-(4-(3-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), A Potent, Selective, and Efficacious Inhibitor of Phosphodiesterase 10A (PDE10A)

被引：34

作者：

Hu, Essa ^{[1
]}

Chen, Ning ^{[1
]}

Bourbeau, Matthew P. ^{[1
]}

Harrington, Paul E. ^{[1
]}

Biswas, Kaustav ^{[1
]}

Kunz, Roxanne K. ^{[1
]}

Andrews, Kristin L. ^{[2
]}

Chmait, Samer ^{[2
]}

Zhao, Xiaoning ^{[5
]}

Davis, Carl ^{[3
]}

Ma, Ji ^{[7
]}

Shi, Jianxia ^{[7
]}

Lester-Zeiner, Dianna ^{[6
]}

Danao, Jean ^{[6
]}

Able, Jessica ^{[6
]}

Cueva, Madelyn ^{[6
]}

Talreja, Santosh ^{[6
]}

Kornecook, Thomas ^{[4
]}

Chen, Hang ^{[6
]}

Porter, Amy ^{[4
]}

Hungate, Randall ^{[1
]}

Treanor, James ^{[4
]}

Allen, Jennifer R. ^{[1
]}

机构：

[1] Amgen Inc, Dept Med Chem, One Amgen Ctr Dr, Thousand Oaks, CA 93012 USA

[2] Amgen Inc, Dept Mol Struct & Characterizat, Thousand Oaks, CA 93012 USA

[3] Amgen Inc, Dept Pharmacokinet & Drug Metab, Thousand Oaks, CA 93012 USA

[4] Amgen Inc, Dept Neurosci, Thousand Oaks, CA 93012 USA

[5] Amgen Inc, Dept Mol Struct & Characterizat, San Francisco, CA 94080 USA

[6] Amgen Inc, Dept Neurosci, San Francisco, CA 94080 USA

[7] Amgen Inc, Dept Pharmacokinet & Drug Metab, San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 15期

关键词：

STRUCTURE-BASED DESIGN; SCHIZOPHRENIA; STRIATUM; DISEASE; MODELS; SERIES; BRAIN; DRUGS;

D O I：

10.1021/jm500713j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-acetyl piperazine 2 were changed by a single atom to tetrahydropyran 3 and N-acetyl piperidine 5. A second single atom modification from pyrazines 3 and 5 to pyridines 4 and 6 improved the inhibitory activity of 4 but not 6. In the in vivo LC-MS/MS target occupancy (TO) study at 10 mg/kg, 3, 5, and 6 achieved 86-91% occupancy of PDE10A in the brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral model were observed in a dose dependent manner. With superior in vivo TO, in vivo efficacy and in vivo PK profiles in multiple preclinical species, compound 5 (AMG 579) was advanced as our PDE10A clinical candidate.

引用

页码：6632 / 6641

页数：10

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