ABSTRACT
A variety of basic, heterocyclic templates has been reported as potassium-competitive, acid pump antagonists. Herein, we report a comparison of potencies of these templates and others to establish which offers the best start point for further systematic optimisation. Modifications were carried out to improve the developability profile of the more potent 1H-pyrrolo[2,3-c]pyridine template, affording molecules with improved overall in vitro characteristics versus the reported clinical candidate AR-H047108, and comparable to the clinically efficacious AZD-0865.
Subject(s)
Heterocyclic Compounds/pharmacology , Proton Pump Inhibitors , Pyridines/pharmacology , Binding, Competitive , Drug Design , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Acid pump antagonists (APAs) such as the imidazo[1,2-a]pyridine AZD-0865 2 have proven efficacious at low oral doses in acid related gastric disorders. Herein we describe some of the broader SAR in this class of molecule and detail the discovery of an imidazo[1,2-a]pyridine 15 which has excellent efficacy in animal models of gastric acid secretion following oral administration, as well as a good overall developability profile. The discovery strategy focuses on use of heteroaryl and heterocyclic substituents at the C-6 position and optimization of developability characteristics through modulation of global physico-chemical properties.
Subject(s)
Proton Pump Inhibitors , Proton Pump Inhibitors/chemistry , Pyridines/chemistry , Administration, Oral , Animals , Dogs , H(+)-K(+)-Exchanging ATPase/metabolism , Humans , Hydrogen-Ion Concentration , Proton Pump Inhibitors/chemical synthesis , Proton Pump Inhibitors/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Rats , 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 pyridone-N-benzyl-propanoic acids have been optimised to afford potent orally bioavailable VLA-4 antagonists.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Pyridones/pharmacology , Administration, Oral , Animals , Pyridones/administration & dosage , Pyridones/pharmacokinetics , RatsABSTRACT
A novel series of pyridone inhibitors has been identified through pharmacophore analysis, as potent antagonists of VLA-4.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Pyridones/chemical synthesis , Pyridones/pharmacology , Binding Sites , Drug Design , Structure-Activity Relationship , Vascular Cell Adhesion Molecule-1/metabolismABSTRACT
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 6-aryl-pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3).
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Pyridines/chemical synthesis , Animals , Binding Sites , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Pyridines/pharmacology , Structure-Activity Relationship , WaterABSTRACT
A series of 6-heteroaryl-pyrazolo[3,4-b]pyridines has been optimised to afford potent inhibitors of Glycogen Synthase Kinase-3 (GSK-3). These analogues display excellent selectivity over the closely related Cyclin Dependent Kinase-2 (CDK-2).
