Jason W. Szewczyk

Design of potent and selective GPR119 agonists for type II diabetes.

Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC(50)=3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58).

Nuclear Hormone Receptor Modulators for the Treatment of Diabetes and Dyslipidemia

Publisher Summary Concerted endeavors to identify superior methods to treat multiple aspects of the metabolic syndrome have fueled a veritable renaissance in the field of nuclear hormone receptor (NHR) modulators. These biological targets, which include the peroxisome-proliferator-activated receptors (PPAR), retinoid X receptor (RXR), liver X receptor (LXR), and farnesoid X receptor (FXR), are recognized as pharmaceutically viable intervention points. The PPAR subtype family comprises three members (α, γ, and δ) that function as lipid sensors and transcriptional regulators of nutrient homeostasis. RXR heterodimers with PPAR, LXR, and FXR are known to activate gene transcription in the presence of an agonist for either of the partnered receptors. The NHR LXR comprises two subtypes—LXRa (NR1H3) and LXRb (NR1H2)—acting as intracellular oxysterol sensors that regulate the expression of genes involved in lipid metabolism. FXR is an NHR acting as a physiological sensor for bile acids by controlling genes regulating their metabolism and transport. The repression of key genes, Cyp7A1 and Cyp8B1, by FXR holds much of its promise as a therapeutic target.

Chapter 7:Recent Advances in the Discovery of GPR119 Agonists

The increased worldwide prevalence of diabetes mellitus (DM) in recent decades has been accompanied by an increase in the number of available pharmacologic therapies used to treat the disease. Differentiation of the available drugs is therefore an important factor for managing the disease effectivel...

Discovery of phenyl acetamides as potent and selective GPR119 agonists

The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its projected human dose was much lower than that of the recently reported structurally-related benzyloxy compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate) efficacy studies.