Fatty acids beyond their role as an endogenous energy source and storage are increasingly considered as signaling molecules regulating various physiological effects in metabolism and inflammation. Accordingly, the molecular targets involved in formation and physiological activities of fatty acids hold significant therapeutic potential. A number of these fatty acid targets are addressed by some of the oldest and most widely used drugs such as cyclooxygenase inhibiting NSAIDs, whereas others remain unexploited. Compounds orthosterically binding to proteins that endogenously bind fatty acids are considered as fatty acid mimetics. On the basis of their structural resemblance, fatty acid mimetics constitute a family of bioactive compounds showing specific binding thermodynamics and following similar pharmacokinetic mechanisms. This perspective systematically evaluates targets for fatty acid mimetics, investigates their common structural characteristics, and highlights demands in their discovery and design. In summary, fatty acid mimetics share particularly favorable characteristics justifying the conclusion that their therapeutic potential vastly outweighs the challenges in their design.

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.

The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferatoractivated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist explaining the pleiotropic effects and report its systematic structure−activity relationship analysis with the discovery of specific molecular determinants driving activity on PPARs and RXRs. We have designed close analogues of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacological tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist revealed activity in vivo and active concentrations in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery.

As universal heterodimer partners of many nuclear receptors, the retinoid X receptors (RXRs) constitute key transcription factors. They regulate cell proliferation, differentiation, inflammation, and metabolic homeostasis and have recently been proposed as potential drug targets for neurodegenerative and inflammatory diseases. Owing to the hydrophobic nature of RXR ligand binding sites, available synthetic RXR ligands are lipophilic, and their structural diversity is limited. Here, we disclose the computer-assisted discovery of a novel RXR agonist chemotype and its systematic optimization toward potent RXR modulators. We have developed a nanomolar RXR agonist with high selectivity among nuclear receptors and superior physicochemical properties compared to classical rexinoids that appears suitable for in vivo applications and as lead for future RXR-targeting medicinal chemistry.

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