Growing evidence suggests an essential role of neuroinflammation in behavioral abnormalities associated with hepatic encephalopathy (HE). Here, we report the involvement of autotaxin−lysophosphatidic acid (LPA) signaling in HE's pathogenesis. We demonstrate that the autotaxin (ATX) inhibitor PF-8380 attenuates neuroinflammation and improves neurological dysfunction in the mouse model of HE. In the thioacetamide (TAA)-induced model of HE, we found a twofold increase in the levels of ammonia in the brain and in plasma along with a significant change in HE-related behavioral parameters. Mice with HE show an increased brain weight, increased levels of tumor necrosis factor-α (TNF-α), IL-1β (interleukin-1β), interleukin-6 (IL-6), and LPA 18:0 in the cerebral cortex and hippocampus, and increased levels of LPA 18:0 in plasma. Treatment with the autotaxin inhibitor (ATXi) did not affect liver injury, as we observed no change in liver function markers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) and no change in ammonia levels in the brain and plasma. However, ATXi treatment significantly ameliorated the neuroinflammation, reduced the levels of LPA 18:0 in the cerebral cortex and hippocampus in the brain and plasma, and reduced brain edema and the levels of IL1β, IL-6, and TNF-α. The neurobehavioral symptoms for HE such as the cognitive and motor function deficit and overall clinical grading score were significantly improved in ATXi-treated mice. Mouse astrocytes and microglia stimulated with NH 4 CL with or without ATXi showed significant attenuation of oxidative stress and the neuroinflammatory effect of NH4CL in ATXi-treated cells.

Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = −13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = −9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC 50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 μM in human embryonic kidney cells), metabolically stable against human liver microsomes (CL int = 15.6 μl/min/mg; T 1/2 = 113.2 min) with solubility of 4.82 μM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.

Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin-based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold-hopping approach combined with docking studies for putative-binding interactions with Plasmodium falciparum phosphatidylinositol-4-kinase (PfPI4K) target. The docking results steered to the synthesis of compound 1 [5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl) phenyl)-3H-imidazo[4,5-b]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME-PK studies. Combined with potent antimalarial activity of compound 1 (Pf3D7 IC 50 = 29 nM) with meager in vitro intrinsic clearance, moderate plasma-protein binding, and acceptable permeability, compound 1 displayed sustained exposure and high oral bioavailability in mice and can thus have the potential as next generation PI4K inhibitor for in vivo studies.