Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics.

The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure-activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and in vivo profiling revealed superior PK properties compared to current RXR agonists. The optimized compounds were highly selective for RXR activation and induced RXR-regulated gene expression in native cellular and in vivo settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR.

Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain.

The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure-activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid (22b, SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo.

Characterization of the molecular mechanism of 5-lipoxygenase inhibition by 2-aminothiazoles.

5-Lipoxygenase (5-LO, EC1.13.11.34) has been implicated in the pathogenesis of inflammatory and immune diseases. Recently, aminothiazole comprising inhibitors have been discovered for this valuable target. Yet, the molecular mode of action of this class of substances is only poorly understood. Here, we present the detailed molecular mechanism of action of the compound class and the in vitro pharmacological profile of two lead compounds ST-1853 and ST-1906. Mechanistic studies with recombinant proteins as well as intact cell assays enabled us to define this class as a novel type of 5-LO inhibitors with unique characteristics. The parent compounds herein presented a certain reactivity concerning oxidation and thiol binding: Unsubstituted aminophenols bound covalently to C159 and C418 of human 5-LO. Yet, dimethyl substitution of the aminophenol prevented this reactivity and slowed down phase II metabolism. Both ST-1853 and ST-1906 confirmed their lead likeness by retaining their high potency in physiologically relevant 5-LO activity assays, high metabolic stability, high specificity and non-cytotoxicity.

Development of novel aminothiazole-comprising 5-LO inhibitors.

BACKGROUND: Leukotrienes are pivotal lipid mediators in various immune and inflammatory reactions. Herein, 5-LO is a validated target. 2-Aminothiazoles, as a privileged structure, implicate known 5-LO inhibitors like ST-1083 (IC50 [polymorphonuclear leukocytes (PMNL)] = 0.68 µM), yet deep structure-activity relationships (SAR) have not been established. MATERIALS & METHODS: Compounds were synthesized via Hantzsch thiazole synthesis. Inhibitory activities were evaluated using intact PMNL and purified 5-LO together with cytotoxicity measurements in U937 cells. RESULTS: We introduced novel functionalities at 2-, 3-, 4- and 5-position of the 2-aminothiazole scaffold and conducted bioisosteric replacement to optimize the parent scaffold. SARs of the 2-aminothiazole scaffold were deduced and extended primarily for inhibition of the 5-LO enzyme. CONCLUSION: SAR studies provided at least two optimized leads (ST-1853, ST-1906) with high potency (IC50 [polymorphonuclear leukocytes] = 0.05 µM), specificity and noncytotoxic behavior.