ABSTRACT
GPR40 (FFAR1 or FFA1) is a G protein-coupled receptor, primarily expressed in pancreatic islet ß-cells and intestinal enteroendocrine cells. When activated by fatty acids, GPR40 elicits increased insulin secretion from islet ß-cells only in the presence of elevated glucose levels. Towards this end, studies were undertaken towards discovering a novel GPR40 Agonist whose mode of action is via Positive Allosteric Modulation of the GPR40 receptor (AgoPAM). Efforts were made to identify a suitable GPR40 AgoPAM tool molecule to investigate mechanism of action and de-risk liver toxicity of GPR40 AgoPAMs due to reactive acyl-glucuronide (AG) metabolites.
Subject(s)
Indans/metabolism , Receptors, G-Protein-Coupled/agonists , Drug Design , HumansABSTRACT
A series of biaryl chromans exhibiting potent and selective agonism for the GPR40 receptor with positive allosteric modulation of endogenous ligands (AgoPAM) were discovered as potential therapeutics for the treatment of type II diabetes. Optimization of physicochemical properties through modification of the pendant aryl rings resulted in the identification of compound AP5, which possesses an improved metabolic profile while demonstrating sustained glucose lowering.
ABSTRACT
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Cardiomegaly/chemically induced , Glucose/metabolism , Homeostasis/drug effects , Imidazoles/pharmacology , Pyridines/pharmacology , Animals , Benzimidazoles , Blood Glucose/drug effects , Fasting , Glycogen/metabolism , Hypoglycemia/chemically induced , Imidazoles/adverse effects , Imidazoles/chemistry , Insulin/pharmacology , Macaca mulatta , Male , Mice , Mice, Inbred C57BL , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Pyridines/adverse effects , Pyridines/chemistryABSTRACT
SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model.
Subject(s)
ERG1 Potassium Channel/metabolism , Potassium Channel Blockers/chemistry , Potassium Channels, Inwardly Rectifying/antagonists & inhibitors , Animals , Disease Models, Animal , Dogs , ERG1 Potassium Channel/antagonists & inhibitors , Half-Life , Hypertension/drug therapy , Potassium Channel Blockers/pharmacokinetics , Potassium Channel Blockers/therapeutic use , Potassium Channels, Inwardly Rectifying/metabolism , Pyrimidines/chemistry , Rats , Rats, Inbred SHR , Spiro Compounds/chemistry , Structure-Activity Relationship , Thiadiazoles/chemistryABSTRACT
Following the discovery of small molecule acyl piperazine ROMK inhibitors, the acyl octahydropyrazino[2,1-c][1,4]oxazine series was identified. This series displays improved ROMK/hERG selectivity, and as a consequence, the resulting ROMK inhibitors do not evoke QTc prolongation in an in vivo cardiovascular dog model. Further efforts in this series led to the discovery of analogs with improved pharmacokinetic profiles. This new series also retained comparable ROMK potency compared to earlier leads.
Subject(s)
Oxazines/chemistry , Oxazines/pharmacology , Potassium Channels, Inwardly Rectifying/antagonists & inhibitors , Animals , Diuresis/drug effects , Dogs , Heart Failure/drug therapy , Humans , Hypertension/drug therapy , Macaca mulatta , Oxazines/pharmacokinetics , Potassium Channels, Inwardly Rectifying/metabolism , Rats, Sprague-Dawley , Transcriptional Regulator ERG/antagonists & inhibitors , Transcriptional Regulator ERG/metabolismABSTRACT
Following the discovery of small molecule acyl piperazine ROMK inhibitors and their initial preclinical validation as a novel diuretic agent, our group set out to discover new ROMK inhibitors with reduced risk for QT effects, suitable for further pharmacological experiments in additional species. Several strategies for decreasing hERG affinity while maintaining ROMK inhibition were investigated and are described herein. The most promising candidate, derived from the newly discovered 4-N-heteroaryl acetyl series, improved functional hERG/ROMK ratio by >10× over the previous lead. In vivo evaluation demonstrated comparable diuretic effects in rat with no detectable QT effects at the doses evaluated in an in vivo dog model.
