Abstract
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.
MeSH terms
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Administration, Oral
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Animals
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Antipsychotic Agents / chemical synthesis
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Antipsychotic Agents / chemistry*
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Antipsychotic Agents / pharmacology
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry*
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Benzimidazoles / pharmacology
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Biological Availability
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Brain / metabolism
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Dogs
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Humans
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Male
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Motor Activity / drug effects
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / chemistry*
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Phosphodiesterase Inhibitors / pharmacology
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Phosphoric Diester Hydrolases / chemistry
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Phosphoric Diester Hydrolases / metabolism*
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Primates
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Protein Conformation
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Pyrazines / chemical synthesis
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Pyrazines / chemistry*
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Pyrazines / pharmacology
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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Antipsychotic Agents
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Benzimidazoles
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Phosphodiesterase Inhibitors
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Pyrazines
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PDE10A protein, human
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Phosphoric Diester Hydrolases
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1-(4-(3-(4-(1H-benzo(d)imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone