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)
| Autor: | Kaustav Biswas, Ning Chen, Ji Ma, Xiaoning Zhao, Randall W. Hungate, Carl Davis, Jessica Able, Madelyn Cueva, James J. S. Treanor, Matthew P. Bourbeau, Samer Chmait, Paul E. Harrington, Dianna Lester-Zeiner, Roxanne Kunz, Jianxia Shi, Hang Chen, Jennifer R. Allen, Amy Porter, Kristin L. Andrews, Essa Hu, Jean Danao, Santosh Talreja, Thomas Kornecook |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Primates Stereochemistry Phosphodiesterase Inhibitors Protein Conformation Administration Oral Biological Availability Motor Activity Rats Sprague-Dawley chemistry.chemical_compound Structure-Activity Relationship Dogs In vivo Morpholine Drug Discovery Potency Animals Humans Phosphoric Diester Hydrolases Phosphodiesterase Brain Tetrahydropyran Piperazine chemistry Pyrazines Molecular Medicine Benzimidazoles PDE10A Piperidine Antipsychotic Agents |
| Zdroj: | Journal of medicinal chemistry. 57(15) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|