AMG 579,
A Potent, Selective, and Efficacious Inhibitor of Phosphodiesterase 10A (PDE10A)
http://pubs.acs.org/doi/abs/10.1021/jm500713j?journalCode=jmcmar
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.
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