ABSTRACT
This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.
Subject(s)
Benzazepines/chemistry , Histamine H3 Antagonists/chemistry , Receptors, Histamine H3/chemistry , Animals , Benzazepines/pharmacokinetics , Dogs , Half-Life , Haplorhini , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Male , Microsomes, Liver/metabolism , Niacinamide/analogs & derivatives , Niacinamide/chemistry , Niacinamide/pharmacokinetics , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.
Subject(s)
Benzazepines/chemistry , Histamine H3 Antagonists/chemistry , Receptors, Histamine H3/chemistry , Animals , Benzazepines/chemical synthesis , Benzazepines/pharmacokinetics , Cytochrome P-450 CYP2D6/chemistry , Cytochrome P-450 CYP2D6/metabolism , Drug Evaluation, Preclinical , Half-Life , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Protein Binding , Rats , Receptors, Histamine H3/genetics , Receptors, Histamine H3/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Structure-Activity RelationshipABSTRACT
A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement.
Subject(s)
Cognition/drug effects , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/drug effects , Animals , Dogs , Nicotinic Agonists/chemistry , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A series of α7 nicotinic acetylcholine receptor full agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Early lead 1 was found to have a limited therapeutic index with respect to its potential for cardiovascular side effects. Further optimisation of this series led to the identification of 22 a potent full agonist showing efficacy at a dose of 0.1mg/kg in the novel object recognition model of cognition enhancement. Comparison of 1 with 22 demonstrated the latter to have an improved oral pharmacokinetic profile and cardiovascular therapeutic index.
Subject(s)
Cognition/drug effects , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/drug effects , Animals , Dose-Response Relationship, Drug , Rabbits , Receptors, Nicotinic/chemistry , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A pharmacophore model was built, based on known CGRP receptor antagonists, and this was used to aid the identification of novel leads. Analogues were designed, modelled and synthesised which incorporated alternative 'LHS' fragments linked via either an amide or urea to a privileged 'RHS' fragment commonly found in CGRP receptor antagonists. As a result a novel series of oxadiazole CGRP receptor antagonists has been identified and the subsequent optimisation to enhance both potency and bioavailability is presented.
Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Drug Design , Migraine Disorders/drug therapy , Oxadiazoles/chemical synthesis , Oxadiazoles/therapeutic use , Administration, Oral , Animals , Models, Molecular , Molecular Structure , Oxadiazoles/chemistry , RatsABSTRACT
A series of ketopiperazines were prepared and evaluated for their activity as histamine H 3 antagonists. From investigation of the tertiary basic center in the aminopropyloxyphenyl template, the 2( R)-methylpyrrolidine was identified as the most potent amine. In the more rigid piperidineoxyphenyl template the N-cyclobutyl group was the most potent amine. The 4-fluorobenzyol, 4-cyanobenzoyl, and 2,4-difluorobenzoyl groups provided good pharmacokinetic profiles for the various amides. The PSA and log D values of these compounds suggested low brain penetration. The compounds had very high selectivity over other receptors and did not inhibit hepatic cytochrome P450, indicating low drug-drug interaction potential. Compound 22i was identified as the best compound of this series based on its overall profile of high potency, selectivity, low brain penetration, lack of CYP450 inhibition, high oral bioavailability, and pharmacokinetic properties.
Subject(s)
Brain/metabolism , Histamine H3 Antagonists/chemical synthesis , Piperazines/chemical synthesis , Administration, Oral , Animals , Blood-Brain Barrier/metabolism , CHO Cells , Cerebral Cortex/metabolism , Cricetinae , Cricetulus , Cytochrome P-450 Enzyme System/metabolism , Dogs , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Guinea Pigs , Histamine H3 Antagonists/pharmacokinetics , Histamine H3 Antagonists/pharmacology , Humans , Ileum/drug effects , Ileum/physiology , In Vitro Techniques , Isoenzymes/metabolism , Isometric Contraction/drug effects , Male , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Piperazines/pharmacokinetics , Piperazines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The novel imidazo[4,5-c]pyridine 1,2,5-oxadiazol-3-yl template affords an excellent start point for identification of inhibitors of a number of protein kinases. Here we report on its optimisation for mitogen and stress-activated protein kinase-1 (MSK-1) inhibitory activity, and selectivity over other kinases.
