Sulindac Derivatives That Activate the Peroxisome Proliferator-activated Receptor γ but Lack Cyclooxygenase Inhibition

A series of novel derivatives of the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide were synthesized as potential agonists of the peroxisome proliferator-activated receptor gamma (PPARγ). Nonpolar and aromatic substitutions on the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity. Compound <b>24</b> was as potent a compound as any other in the series with an EC₅₀ of 0.1 μM for the induction of peroxisome proliferator response element (PPRE)-luciferase activity. Direct binding of compound <b>24</b> to PPARγ was demonstrated by the displacement of [³H]troglitazone, a PPARγ agonist, in a scintillation proximity assay. Compound <b>24</b> also stimulated the binding of PPARγ to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPARγ target genes. Taken together, these compounds represent potential leads in the development of novel PPARγ agonists

Substituted 1‑Phenyl-3-(pyridin-2-yl)urea Negative Allosteric Modulators of mGlu₅: Discovery of a New Tool Compound VU0463841 with Activity in Rat Models of Cocaine Addiction

Cocaine is a powerful and highly addictive stimulant that disrupts the normal reward circuitry in the central nervous system (CNS), producing euphoric effects. Cocaine use can lead to acute and life threatening emergencies, and abuse is associated with increased risk for contracting infectious diseases. Though certain types of behavioral therapy have proven effective for treatment of cocaine addiction, relapse remains high, and there are currently no approved medications for the treatment of cocaine abuse. Evidence has continued to accumulate that indicates a critical role for the metabotropic glutamate receptor subtype 5 (mGlu₅) in the modulation of neural circuitry associated with the addictive properties of cocaine. While the small molecule mGlu₅ negative allosteric modulator (NAM) field is relatively advanced, investigation into the potential of small molecule mGlu₅ NAMs for the treatment of cocaine addiction remains an area of high interest. Herein we describe the discovery and characterization of a potent and selective compound <b>29</b> (VU0463841) with good CNS exposure in rats. The utility of <b>29</b> (VU0463841) was demonstrated by its ability to attenuate drug seeking behaviors in relevant rat models of cocaine addiction

Design and Synthesis of mGlu₂ NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core

Herein, we detail the optimization of the mGlu₂ negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu₂ NAM scaffold. This new chemotype not only affords potent and selective mGlu₂ inhibition, as exemplified by VU6001966 (mGlu₂ IC₅₀ = 78 nM, mGlu₃ IC₅₀ > 30 μM), but also excellent central nervous system (CNS) penetration (<i>K</i>_p = 1.9, <i>K</i>_p,uu = 0.78), a feature devoid in all previously disclosed mGlu₂ NAMs (<i>K</i>_ps ≈ 0.3, <i>K</i>_p,uus ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu₂ PET tracer development