ABSTRACT
Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.
Subject(s)
Enzyme Activators/chemistry , Glucokinase/metabolism , Pyrimidinones/chemical synthesis , Allosteric Regulation , Amino Acid Motifs , Animals , Binding Sites , Models, Molecular , Pyrimidinones/chemistry , RatsABSTRACT
A novel GPR119 agonist based on the 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole scaffold was designed through lead optimization starting from pyrazole-based GPR119 agonist 1. The design is centered on the conformational restriction of the core scaffold, while minimizing the change in spatial relationships of two key pharmacophoric elements (piperidine-carbamate and aryl sulfone).
Subject(s)
Pyrazoles/chemistry , Receptors, G-Protein-Coupled/agonists , Carbamates/chemistry , Humans , Piperidines/chemistry , Protein Binding , Pyrazoles/chemical synthesis , Pyrazoles/metabolism , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy.
Subject(s)
Drug Design , Glucokinase/chemistry , Hypoglycemic Agents/chemical synthesis , Indazoles/chemistry , Pyrazines/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemistry , Administration, Oral , Animals , Cell Line, Tumor , Diabetes Mellitus, Type 2/drug therapy , Glucokinase/metabolism , Glucose Tolerance Test , Half-Life , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Indazoles/chemical synthesis , Indazoles/pharmacokinetics , Indazoles/therapeutic use , Insulin/metabolism , Kinetics , Protein Binding , Pyrazines/pharmacokinetics , Pyrazines/therapeutic use , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10 n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in logP and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.
Subject(s)
Azetidines/chemistry , Piperidines/chemistry , Receptors, Ghrelin/agonists , Animals , Azetidines/chemical synthesis , Azetidines/pharmacokinetics , Drug Inverse Agonism , Humans , Microsomes, Liver/metabolism , Rats , Receptors, Ghrelin/metabolism , Structure-Activity RelationshipABSTRACT
A series of 2-heteroaryl-4-arylimidazoles with potent in vitro activity at the NPY5 receptor was developed. Introduction of electron-withdrawing groups on the 4-aryl ring led to a significant improvement of in vitro potency. Several analogues from this series had anorectic activity in rodent feeding models, but were also found to have undesired behavioral effects in spontaneous locomotor activity.
Subject(s)
Imidazoles/chemistry , Imidazoles/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Animals , Behavior, Animal/drug effects , Feeding Behavior/drug effects , Rats , Structure-Activity RelationshipABSTRACT
Beginning with carbazole 1a, the amide and alkyl substituents were optimized to maintain potency while adding solubilizing groups. Efforts to replace the 3-amino-9-ethylcarbazole core, a known carcinogen, used the SAR generated in the carbazole series for guidance and led to the synthesis of a number of core-modified analogues. In addition, an isosteric series, in which the amide was replaced with an imidazole, was prepared. Two potent new series lacking the putative toxicophore were identified from these endeavors.
Subject(s)
Amides/chemistry , Amides/pharmacology , Carbazoles/chemistry , Carbazoles/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Animals , Calcium/chemistry , Calcium/pharmacology , Eating/drug effects , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Male , Radioligand Assay , Rats , Rats, Sprague-Dawley , Solubility , Structure-Activity RelationshipABSTRACT
In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the beta(1)-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compounds with enhanced TR beta affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis.
