ABSTRACT
We report the identification of a novel biaryl template for H(+)/K(+) ATPase inhibition. Evaluation of critical SAR features within the biaryl imidazole framework and the use of pharmacophore modelling against known imidazopyridine and azaindole templates suggested that the geometry of the molecule is key to achieving activity. Herein we present our work optimising the potency of the molecule through modifications and substitutions to each of the ring systems. In particular sub-micromolar potency is achieved with (4b) presumably through a proposed intramolecular hydrogen bond that ensures the required imidazole basic centre is appropriately located.
Subject(s)
Drug Discovery/methods , Imidazoles/chemistry , Proton Pump Inhibitors , H(+)-K(+)-Exchanging ATPase/metabolism , Imidazoles/metabolism , Imidazoles/pharmacology , Structure-Activity RelationshipABSTRACT
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
High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats.
