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 Phos

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• 作者：Essa Hu ; Ning Chen ; Matthew P. Bourbeau ; Paul E. Harrington ; Kaustav Biswas ; Roxanne K. Kunz ; Kristin L. Andrews ; Samer Chmait ; Xiaoning Zhao ; Carl Davis ; Ji Ma ; Jianxia Shi ; Dianna Lester-Zeiner ; Jean Danao ; Jessica Able ; Madelyn Cueva ; Santosh Talreja ; Thomas Kornecook ; Hang Chen ; Amy Porter ; Randall Hungate ; James Treanor ; Jennifer R. Allen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 14, 2014
• 年：2014
• 卷：57
• 期：15
• 页码：6632-6641
• 全文大小：392K
• ISSN：1520-4804

文摘

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鈥揗S/MS target occupancy (TO) study at 10 mg/kg, 3, 5, and 6 achieved 86鈥?1% 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.