title: 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).
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.
authors: Department of Medicinal Chemistry, ‡Department of Molecular Structure and Characterization, §Department of Pharmacokinetics and Drug Metabolism, ∥Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States.
authors: Essa
authors: E
authors: Hu
authors: Ning
authors: N
authors: Chen
authors: Matthew P
authors: MP
authors: Bourbeau
authors: Paul E
authors: PE
authors: Harrington
authors: Kaustav
authors: K
authors: Biswas
authors: Roxanne K
authors: RK
authors: Kunz
authors: Kristin L
authors: KL
authors: Andrews
authors: Samer
authors: S
authors: Chmait
authors: Xiaoning
authors: X
authors: Zhao
authors: Carl
authors: C
authors: Davis
authors: Ji
authors: J
authors: Ma
authors: Jianxia
authors: J
authors: Shi
authors: Dianna
authors: D
authors: Lester-Zeiner
authors: Jean
authors: J
authors: Danao
authors: Jessica
authors: J
authors: Able
authors: Madelyn
authors: M
authors: Cueva
authors: Santosh
authors: S
authors: Talreja
authors: Thomas
authors: T
authors: Kornecook
authors: Hang
authors: H
authors: Chen
authors: Amy
authors: A
authors: Porter
authors: Randall
authors: R
authors: Hungate
authors: James
authors: J
authors: Treanor
authors: Jennifer R
authors: JR
authors: Allen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D004285:Dogs; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011323:Primates; D011487:Protein Conformation; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D001562:Benzimidazoles; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; C000594998:1-(4-(3-(4-(1H-benzo(d)imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone