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
A new series of 2-(benzyloxy)benzamides are presented that are potent functional antagonists of TRPM8 and possess improved LipE and LE compared to the original lead. They were discovered through a series of compound libraries and we present a powerful visualization method for the chemical space explored with each library. Remarkably this new series originated from the highest risk design strategy where compounds were synthesised with the least degree of similarity to the lead structure.
Subject(s)
Benzamides/pharmacology , TRPM Cation Channels/antagonists & inhibitors , Animals , Drug Design , Drug Discovery , Humans , Rats , Structure-Activity RelationshipABSTRACT
Optimisation of the potency of a bicyclic CRF antagonist whilst retaining metabolic stability is described. A core change and incorporation of metabolically stable lipophilic groups resulted in a further potency gain without increasing metabolic liability. Pharmacological investigation of binding kinetics led to the identification of compound 25, a sub-nanomolar CRF-1 antagonist with slow dissociation kinetics and an encouraging pharmacokinetic profile.
Subject(s)
Corticotropin-Releasing Hormone/antagonists & inhibitors , Purines/chemistry , Purines/metabolism , Animals , Corticotropin-Releasing Hormone/metabolism , Drug Discovery , Humans , Kinetics , Microsomes, Liver/metabolism , Protein Binding , Purines/pharmacokinetics , Purines/pharmacology , RatsABSTRACT
Balancing potency and metabolic stability in a target which favours lipophilic ligands is a considerable challenge. Here we describe two strategies employed to achieve this balance in a series of pyrazolopyrimidine CRF antagonists: moderation of lipophilicity, and incorporation of a metabolically stable lipophilic group.
Subject(s)
Pyrimidines/chemistry , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Humans , Ligands , Microsomes, Liver/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR's which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.
Subject(s)
Amides/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , Piperidines/chemical synthesis , Piperidines/pharmacology , Anti-HIV Agents/chemistry , Combinatorial Chemistry Techniques , Drug Design , Drug Discovery , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/drug effects , HIV-1/drug effects , Humans , Microsomes, Liver/drug effects , Molecular Structure , Piperidines/chemistry , Structure-Activity RelationshipABSTRACT
Self-indicating methylisocyanate resin, which functions as both a scavenger and an indicator for amines, was used for in-situ reaction monitoring and purification of a urea based library.
