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1.
J Med Chem ; 57(24): 10512-26, 2014 Dec 26.
Article in English | MEDLINE | ID: mdl-25423286

ABSTRACT

Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.


Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Hepatocytes/drug effects , Ketones/metabolism , Lipogenesis/drug effects , Microsomes/drug effects , Acetyl-CoA Carboxylase/metabolism , Adult , Animals , Area Under Curve , Cells, Cultured , Cross-Over Studies , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Dogs , Double-Blind Method , Hepatocytes/cytology , Humans , Male , Malonyl Coenzyme A/metabolism , Microsomes/metabolism , Middle Aged , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Rats, Wistar , Structure-Activity Relationship , Young Adult
2.
J Med Chem ; 50(21): 5202-16, 2007 Oct 18.
Article in English | MEDLINE | ID: mdl-17887659

ABSTRACT

The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.


Subject(s)
Diabetes Mellitus/drug therapy , Obesity/drug therapy , Quinazolinones/chemical synthesis , Receptors, Ghrelin/antagonists & inhibitors , Administration, Oral , Animals , Binding, Competitive , Blood Glucose/analysis , Cell Line , Eating/drug effects , Glucose Tolerance Test , Humans , Male , Mice , Mice, Inbred C57BL , Quinazolinones/chemistry , Quinazolinones/pharmacology , Radioligand Assay , Rats , Rats, Wistar , Stereoisomerism , Structure-Activity Relationship , Weight Loss/drug effects
3.
Endocrinology ; 148(11): 5175-85, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17656463

ABSTRACT

Ghrelin, through action on its receptor, GH secretagogue receptor type 1a (GHS-R1a), exerts a variety of metabolic functions including stimulation of appetite and weight gain and suppression of insulin secretion. In the present study, we examined the effects of novel small-molecule GHS-R1a antagonists on insulin secretion, glucose tolerance, and weight loss. Ghrelin dose-dependently suppressed insulin secretion from dispersed rat islets. This effect was fully blocked by a GHS-R1a antagonist. Consistent with this observation, a single oral dose of a GHS-R1a antagonist improved glucose homeostasis in an ip glucose tolerance test in rat. Improvement in glucose tolerance was attributed to increased insulin secretion. Daily oral administration of a GHS-R1a antagonist to diet-induced obese mice led to reduced food intake and weight loss (up to 15%) due to selective loss of fat mass. Pair-feeding experiments indicated that weight loss was largely a consequence of reduced food intake. The impact of a GHS-R1a antagonist on gastric emptying was also examined. Although the GHS-R1a antagonist modestly delayed gastric emptying at the highest dose tested (10 mg/kg), delayed gastric emptying does not appear to be a requirement for weight loss because lower doses produced weight loss without an effect on gastric emptying. Consistent with the hypothesis that ghrelin regulates feeding centrally, the anorexigenic effects of potent GHS-R1a antagonists in mice appeared to correspond with their brain exposure. These observations demonstrate that GHS-R1a antagonists have the potential to improve the diabetic condition by promoting glucose-dependent insulin secretion and promoting weight loss.


Subject(s)
Appetite Depressants/therapeutic use , Appetite/drug effects , Glucose Intolerance/drug therapy , Receptors, Ghrelin/antagonists & inhibitors , Weight Loss/drug effects , Animals , Appetite Depressants/pharmacology , Cells, Cultured , Drug Evaluation, Preclinical , Ghrelin/antagonists & inhibitors , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Male , Mice , Mice, Inbred C57BL , Models, Biological , Piperidines/pharmacology , Piperidines/therapeutic use , Quinazolinones/pharmacology , Quinazolinones/therapeutic use , Rats , Rats, Sprague-Dawley , Rats, Wistar
4.
Bioorg Med Chem Lett ; 17(10): 2869-73, 2007 May 15.
Article in English | MEDLINE | ID: mdl-17400452

ABSTRACT

Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.


Subject(s)
Insulin/metabolism , Islets of Langerhans/drug effects , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Quinolines/pharmacology , Drug Design , Humans , Insulin Secretion , Islets of Langerhans/metabolism , Molecular Structure , Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases/drug effects , Quinolines/chemical synthesis , Quinolines/chemistry , Structure-Activity Relationship
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