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 backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.
Subject(s)
Imidazolines/pharmacology , Purinergic Antagonists/pharmacology , Receptors, Purinergic P2X7/drug effects , Administration, Oral , Animals , Biological Availability , Half-Life , Haplorhini , Imidazolines/administration & dosage , Imidazolines/chemistry , Imidazolines/pharmacokinetics , Purinergic Antagonists/administration & dosage , Purinergic Antagonists/chemistry , Purinergic Antagonists/pharmacokinetics , RatsABSTRACT
A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.
Subject(s)
Amides/pharmacology , Purinergic P2 Receptor Antagonists/pharmacology , Pyrrolidonecarboxylic Acid/chemistry , Receptors, Purinergic P2X7/drug effects , Amides/chemistry , Drug Discovery , Models, Molecular , Purinergic P2 Receptor Antagonists/chemistry , Structure-Activity RelationshipABSTRACT
As part of an on-going lead optimisation effort, a cross screening exercise identified an aryl sulphonyl amide hit that was optimised to afford a highly potent series of ghrelin receptor agonists.
Subject(s)
Chemistry, Pharmaceutical/methods , Ghrelin/chemistry , Receptors, Ghrelin/antagonists & inhibitors , Sulfones/chemistry , Administration, Oral , Animals , Biological Availability , Drug Design , Growth Hormone/chemistry , Male , Models, Chemical , Protein Processing, Post-Translational , Rats , Rats, Sprague-Dawley , Receptors, Ghrelin/chemistry , Structure-Activity RelationshipABSTRACT
Modification of the potent imidazole-based B-Raf inhibitor SB-590885 resulted in the identification of a series of furan-based derivatives with enhanced CNS penetration. One such compound, SB-699393 (17), was examined in vivo to challenge the hypothesis that selective B-Raf inhibitors may be of value in the treatment of stroke.
Subject(s)
Central Nervous System/drug effects , Furans/chemical synthesis , Furans/pharmacology , Indans/chemical synthesis , Indans/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Animals , Furans/chemistry , Imidazoles/chemistry , Imidazoles/pharmacology , Indans/chemistry , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Rats , Stroke/drug therapy , Structure-Activity RelationshipABSTRACT
A series of small molecule orally bioavailable ghrelin receptor agonists have been identified through systematic optimisation of a high throughput screening hit.
Subject(s)
Indoles/pharmacology , Receptors, Ghrelin/agonists , Sulfonamides/pharmacology , Administration, Oral , Animals , Biological Availability , Fluorescence , Indoles/chemical synthesis , Male , Molecular Structure , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1B/metabolism , Receptors, Ghrelin/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
A novel triarylimidazole derivative, SB-590885 (33), bearing a 2,3-dihydro-1H-inden-1-one oxime substituent has been identified as a potent and extremely selective inhibitor of B-Raf kinase.
Subject(s)
Imidazoles/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Cyclization , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Proto-Oncogene Proteins B-raf/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of imidazo[4,5-c]pyridines bearing a 1,2,5-oxadiazol-3-ylamine functionality has been developed. These are potent inhibitors of mitogen and stress-activated protein kinase-1.
Subject(s)
Amines/pharmacology , Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Oxadiazoles/pharmacology , Pyridines/pharmacology , Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors , Amines/chemical synthesis , Amines/classification , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/classification , Imidazoles/chemical synthesis , Imidazoles/classification , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/classification , Pyridines/chemical synthesis , Pyridines/classification , 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.
