Comparative molecular profiling of the PPARα/γ activator aleglitazar: PPAR selectivity, activity and interaction with cofactors.

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the expression of genes involved in a variety of physiologic processes, through heterodimerization with retinoid X receptor and complex formation with various cofactors. Drugs or treatment regimens that combine the beneficial effects of PPARα and γ agonism present an attractive therapeutic strategy to reduce cardiovascular risk factors. Aleglitazar is a dual PPARα/γ agonist currently in phase III clinical development for the treatment of patients with type 2 diabetes mellitus who recently experienced an acute coronary event. The potency and efficacy of aleglitazar was evaluated in a head-to-head comparison with other PPARα, γ and δ ligands. A comprehensive, 12-concentration dose-response analysis using a cell-based assay showed aleglitazar to be highly potent, with EC(50) values of 5 nM and 9 nM for PPARα and PPARγ, respectively. Cofactor recruitment profiles confirmed that aleglitazar is a potent and balanced activator of PPARα and γ. The efficacy and potency of aleglitazar are discussed in relation to other dual PPARα/γ agonists, in context with the published X-ray crystal structures of both PPARα and γ.

Piperidinyl-nicotinamides as potent and selective somatostatin receptor subtype 5 antagonists.

Nicotinamides of benzyl-substituted 4-aminopiperidines and their seven-membered analogs of generic structure 2 and 2' have been discovered as potent and selective SST5 antagonists. The activity (K(i)) ranges from 2.4 to 436 nM. Most compounds exhibit decent physicochemical properties and follow a clear SAR pattern. Interestingly enough, the receptor is strongly enantiodiscriminating and binds in the amino-azepane-series only the (R)-enantiomer.

Novel, non-peptidic somatostatin receptor subtype 5 antagonists improve glucose tolerance in rodents.

BACKGROUND: Somatostatin regulates numerous endocrine processes, including glucose homeostasis. The contribution and effects of the 5 somatostatin receptors are still unclear, in part due to the lack of suitable subtype specific receptor antagonists. We explored the effects of two novel, non-peptidic, orally bioavailable somatostatin receptor subtype 5 antagonists named Compound A and Compound B on glycemia in animal models of type 2 diabetes after an initial in vitro characterization. METHODS AND RESULTS: Compound A led to a dose-dependent decrease in glucose and insulin excursions during an OGTT in Zucker (fa/fa) rats after single treatment by up to 17% and 49%, respectively. Diet-induced obese mice showed after three weeks treatment with compounds A and B a dose-dependent decrease of the glucose excursion of up to 45% and 37%, respectively. In contrast to the acute effect observed in Zucker rats, Compound A showed a dose-dependent insulin increase by up to 72%, whereas body weight, liver triglycerides, ALT and AST were dose-dependently decreased. CONCLUSIONS: SSTR5 antagonists have the potential for short- and long-term improvements of the glucose homeostasis in rodent models of type 2 diabetes. Further work on the mechanism and the relevance for human disease is warranted.

Benzoxazole piperidines as selective and potent somatostatin receptor subtype 5 antagonists.

SAR studies of a recently described SST5R selective benzoxazole piperidine lead series are described with particular focus on the substitution pattern on the benzyl and benzoxazole side-chains. Introduction of a second meta substituent at the benzyl unit significantly lowers residual hH1 activity and insertion of substituents onto the benzoxazole periphery entirely removes remaining h5-HT2B activity. Compounds with single digit nM activity, functional antagonism and favorable physicochemical properties endowed with a good pharmacokinetic profile in rats are described which should become valuable tools for exploring the pharmacological role of the SST5 receptor in vivo.