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
This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 5/chemistry , Phosphodiesterase 5 Inhibitors/chemistry , Phosphodiesterase 5 Inhibitors/pharmacokinetics , Pyrimidinones/chemistry , Pyrimidinones/pharmacokinetics , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Administration, Oral , Biological Availability , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Humans , Lower Urinary Tract Symptoms/drug therapy , Lower Urinary Tract Symptoms/etiology , Male , Phosphodiesterase 5 Inhibitors/pharmacology , Prostatic Hyperplasia/complications , Pyrimidinones/pharmacology , Sulfonamides/pharmacologyABSTRACT
A new series of glycine-derived ligands of the α(2)δ subunit of voltage gated calcium channels is described. Several novel compounds (7) based on (6) were prepared that possessed a potency <100 nM in the α(2)δ binding assay.
Subject(s)
Calcium Channels/drug effects , Glycine/chemical synthesis , Ligands , Alkylation , Glycine/chemistry , Glycine/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Protein Subunits/chemistry , Structure-Activity RelationshipABSTRACT
The SAR of a series of novel pyrido[3,4-d]pyramid-4-ylamine mGluR1 antagonists is described. The multiple of the unbound K(i) in cerebrospinal fluid necessary to give morphine like analgesic effects in an electromyograph pinch model in rodents is determined and the effect of structure on CNS penetration examined.
