ABSTRACT
Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.
Subject(s)
Drug Design , Indoles/chemical synthesis , Neuralgia/drug therapy , Oxadiazoles/chemical synthesis , Receptor, Cannabinoid, CB1/agonists , Animals , Brain/blood supply , Brain/metabolism , Caco-2 Cells , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Mice , Oxadiazoles/chemistry , Oxadiazoles/pharmacokinetics , RatsABSTRACT
6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-carbonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10 accumulation assays.
Subject(s)
Cathepsins/antagonists & inhibitors , Nitriles/chemistry , Protease Inhibitors/chemistry , Pyridines/chemistry , Animals , Binding Sites , Cathepsins/metabolism , Cell Line , Crystallography, X-Ray , Humans , Mice , Nitriles/chemical synthesis , Nitriles/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A number of water soluble bis-amino-2,6-dimethoxyphenyl ester derivatives were found to exhibit improved anaesthetic activity in mice relative to propofol 1. Of the analogues disclosed, 44 was further profiled in rodents and found to be a superior agent to propofol for the induction and maintenance of anaesthesia.
Subject(s)
Anesthetics, Intravenous/chemistry , Anesthetics, Intravenous/pharmacology , Esters/chemistry , Esters/pharmacology , Phenols/chemistry , Phenols/pharmacology , Anesthetics, Intravenous/chemical synthesis , Animals , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Electroencephalography/drug effects , Esters/chemical synthesis , Infusions, Intravenous/methods , Male , Mice , Mice, Mutant Strains , Phenols/chemical synthesis , Propofol/pharmacology , Rats , Rats, Wistar , Receptors, GABA-A/drug effects , Solubility , Structure-Activity Relationship , Water/chemistryABSTRACT
A novel series of alpha-amino-acid phenolic ester derivatives containing sulphide, sulphoxide, sulphone, ester and amide side chains were prepared and shown to display potent intravenous anaesthetic activity.