Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity.

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.

Indanylacetic acids as PPAR-delta activator insulin sensitizers.

A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.

PDE-10A inhibitors as insulin secretagogues.

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.

Indanylacetic acid derivatives carrying 4-thiazolyl-phenoxy tail groups, a new class of potent PPAR alpha/gamma/delta pan agonists: synthesis, structure-activity relationship, and in vivo efficacy.

Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moiety as a well-tunable PPAR agonist head group. Here we report the synthesis and structure-activity relationship (SAR) studies of novel aryl tail group derivatives that led to a new class of potent PPAR pan agonists.

Indanylacetic acid derivatives carrying aryl-pyridyl and aryl-pyrimidinyl tail groups--new classes of PPAR gamma/delta and PPAR alpha/gamma/delta agonists.

Modulation of PPAR activities represents an attractive approach for the treatment of diabetes with associated cardiovascular complications. The indanylacetic acid structural motif has proven useful in the generation of potent and tunable PPAR ligands. Modification of the substituents on the linker and the heterocycle tail group allowed for the modulation of the selectivity at the different receptor subtypes.