Hans P. Maerki

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 EC50 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.

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.

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.

New Insights on the Mechanism of PPAR-targeted Drugs

Based on discussions held earlier this year during a United States (US) Food and Drug Administration (FDA) advisory panel meeting, use of rosiglitazone has now been severely restricted in the US and completely suspended in Europe due to concerns over its cardiovascular safety. 2] Rosiglitazone and pioglitazone, the other marketed peroxisome proliferator-activated receptor-gamma (PPARg) agent, both act as full agonists of PPARg and influence the transcription of numerous genes and metabolic pathways, leading to improvements in glycemic control, as well as effects on plasma lipids and biomarkers of inflammation and cardiovascular risk. Conversely, these agents are also associated with adverse effects such as peripheral edema, weight gain, bone fractures, and reversible renal effects. Intriguingly, the increase in cardiovascular events appears to be unique to rosiglitazone, and epitomizes a well-known paradox of these agents: their PPARg transcriptional agonist activity does not always correlate with their efficacy and safety. Pioglitazone is a less potent PPARg agonist than rosiglitazone, yet shows comparable antidiabetic efficacy at the therapeutic dose without evidence of an increased risk of cardiovascular events. The effects of pioglitazone on lipids also appears to be slightly more beneficial than those of rosiglitazone. These differences suggest that each PPAR-targeted drug is unique, and that multiple factors in addition to receptor agonism, such as transcriptional cofactor preferences and gene activation signatures, may be responsible for their therapeutic effects and the balance between efficacy and safety. In support of this hypothesis, recent research by Choi and colleagues revealed a new mechanism of action for PPARg agonists, along with an intriguing new molecular link between obesity, adipose inflammation, and insulin resistance. 7a] In addition to enhancing the transcriptional activity of PPARg, rosiglitazone was found to inhibit the phosphorylation of PPARg at Ser273 by CDK5 (a protein kinase) in adipose tissue, preserving transcription of insulin-response genes (such as adiponectin and adipsin) and correlating with antidiabetic activity (Figure 1). Another PPARg agent, MRL24, was just as effective as rosiglitazone at blocking phosphorylation and improving diabetes in animal models, despite being only a partial PPARg agonist. Taken together, these results suggest that the insulinsensitizing benefits of PPARg agonists are due—at least in part—to their ability to block phosphorylation and not solely to their agonist properties. Furthermore, since CDK5 was activated by inflammatory mediators, the inflammation/insulin resistance axis commonly found in obesity may be explained in part by CDK5/PPARg dysregulation. These new findings have obvious implications for the future of PPARg-targeted drug therapy. In particular, they suggest that past drug discovery efforts, which focused exclusively on potency and agonist activity, may have been misguided, and that researchers should examine other aspects. Optimizing the PPAR subtype interaction profile, as well as maximizing inhibition of PPARg phosphorylation, may lead to the development of agents that retain antidiabetic efficacy but have reduced side effects compared with current PPARg drugs. These findings also have implications for PPAR-targeted drugs that are currently in development. Several PPARg-targeted drugs, including partial agonists and PPARg modulators, are currently in phase 2/3 clinical trials (Table 1). Preliminary reports suggest that the antidiabetic activity of most will be similar to rosiglitazone and pioglitazone, and that some of the PPARg modulators may have reduced side-effect profiles compared with full PPARg agonists. 10] Agents that simultaneously modulate the activity of two or three PPARs, in order to provide complementary activity, are also in development. Although several previous dual PPAR agents failed in late-stage development due to safety concerns, reasons for discontinua[a] Dr. M. B. Wright Department of Vascular and Metabolic Diseases F. Hoffmann-La Roche Ltd. Grenzacherstrasse 124, Basel 4070 (Switzerland) Fax: (+ 41) 61 688 2438 E-mail : matthew.wright@roche.com [b] Dr. U. Grether, Dr. W. Klaus, Dr. B. Kuhn, Dr. H. P. Maerki, Dr. P. Mohr Pharma Research F. Hoffmann-La Roche Ltd. Grenzacherstrasse 124, Basel 4070 (Switzerland) Figure 1. Proposed mechanism whereby PPARg-targeted agents may interfere with PPARg phosphorylation.