ABSTRACT
Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain.
ABSTRACT
A number of libraries were produced to explore the potential of 2,4-diaminopyridine lead 1. The resulting diaminopyridines proved to be potent and selective delta-opioid receptor agonists. Several rounds of lead optimisation using library chemistry identified compound 17 which went on to show efficacy in an electromyography model of neuropathic pain. The structure-activity relationship of the series against the hERG ion channel proved to be a key selectivity hurdle for the series.
Subject(s)
4-Aminopyridine/analogs & derivatives , Chemistry, Pharmaceutical/methods , Ether-A-Go-Go Potassium Channels/chemistry , Receptors, Opioid, delta/agonists , 4-Aminopyridine/chemical synthesis , 4-Aminopyridine/pharmacology , Analgesics, Opioid/pharmacology , Animals , Cell Line , Combinatorial Chemistry Techniques , Drug Design , ERG1 Potassium Channel , Electromyography/methods , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Models, Chemical , Rats , Receptors, Opioid, delta/chemistry , Structure-Activity RelationshipABSTRACT
Avoiding cardiac liability associated with blockade of hERG (human ether a go-go) is key for successful drug discovery and development. This paper describes the work undertaken in the discovery of a potent CCR5 antagonist, maraviroc 34, for the treatment of HIV. In particular the use of a pharmacophore model of the hERG channel and a high throughput binding assay for the hERG channel are described that were critical to elucidate SAR to overcome hERG liabilities. The key SAR involves the introduction of polar substituents into regions of the molecule where it is postulated to undergo hydrophobic interactions with the ion channel. Within the CCR5 project there appeared to be no strong correlation between hERG affinity and physiochemical parameters such as pKa or lipophilicity. It is believed that chemists could apply these same strategies early in drug discovery to remove hERG interactions associated with lead compounds while retaining potency at the primary target.
Subject(s)
Anti-HIV Agents/chemistry , CCR5 Receptor Antagonists , Cyclohexanes/chemistry , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Triazoles/chemistry , Anti-HIV Agents/therapeutic use , Cyclohexanes/therapeutic use , Drug Evaluation, Preclinical , Humans , Maraviroc , Receptors, CCR5/metabolism , Triazoles/therapeutic useSubject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , CCR5 Receptor Antagonists , Cyclobutanes/chemistry , Cyclobutanes/pharmacology , HIV Infections/drug therapy , Anti-HIV Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Cyclobutanes/chemical synthesis , Humans , Inhibitory Concentration 50 , Structure-Activity RelationshipABSTRACT
The discovery of maraviroc 17 is described with particular reference to the generation of high selectivity over affinity for the HERG potassium channel. This was achieved through the use of a high throughput binding assay for the HERG channel that is known to show an excellent correlation with functional effects.
Subject(s)
CCR5 Receptor Antagonists , Ether-A-Go-Go Potassium Channels/metabolism , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line , Chemokine CCL4 , HIV/drug effects , Humans , Macrophage Inflammatory Proteins/antagonists & inhibitors , Macrophage Inflammatory Proteins/metabolism , Models, Molecular , Molecular Structure , Receptors, CCR5/metabolism , Structure-Activity RelationshipABSTRACT
The development of compound 1, a piperidine-based CCR5 receptor antagonist with Type I CYP2D6 inhibition, into the tropane-derived analogue 5, is described. This compound, which is devoid of CYP2D6 liabilities, is a highly potent ligand for the CCR5 receptor and has broad-spectrum activity against a range of clinically relevant HIV isolates. The identification of human ether a-go-go-related gene channel inhibition within this series is described and the potential for QTc interval prolongation discussed. Furthermore, structure activity relationship (SAR) around the piperidine moiety is also described.
