ABSTRACT
The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.
Subject(s)
Benzimidazoles/pharmacology , NAV1.8 Voltage-Gated Sodium Channel/metabolism , Voltage-Gated Sodium Channel Blockers/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Drug Design , HEK293 Cells , Humans , Molecular Structure , Solubility , Structure-Activity Relationship , Voltage-Gated Sodium Channel Blockers/chemical synthesis , Voltage-Gated Sodium Channel Blockers/chemistry , Voltage-Gated Sodium Channel Blockers/pharmacokineticsABSTRACT
Introduction of selected amine containing side chains into the 3-position of N',2-diphenylquinoline-4-carbohydrazide based NK3 antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hI(Kr) affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ(90) 7 mg/kg po; plasma Occ(90) 0.4 microM) and has good selectivity and excellent PK properties.
Subject(s)
Fluorine/chemistry , Hydrazines/chemistry , Neurotransmitter Agents/pharmacology , Piperazines/chemistry , Quinolines/chemistry , Receptors, Neurokinin-3/antagonists & inhibitors , Administration, Oral , Animals , CHO Cells , Cricetinae , Dose-Response Relationship, Drug , Fluorine/pharmacology , Hydrazines/pharmacology , Piperazines/pharmacology , Quinolines/pharmacology , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog and functional selectivity for the GABA(A)alpha2 and -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.
Subject(s)
Anxiety Disorders/drug therapy , GABA-A Receptor Agonists , Pyrimidines/pharmacology , Administration, Oral , Animals , Binding Sites , Biological Availability , Cell Line , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Molecular Structure , Patch-Clamp Techniques , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Receptors, GABA-A , Structure-Activity RelationshipABSTRACT
A series of tricyclic pyridones has been evaluated as benzodiazepine site ligands with functional selectivity for the alpha(3) over the alpha(1) containing subtype of the human GABA(A) receptor ion channel. This investigation led to the identification of a high affinity, functionally selective, orally bioavailable benzodiazepine site ligand that demonstrated activity in rodent anxiolysis models and reduced sedation relative to diazepam.
