Optimization of N-Phenylpropenoyl-l-amino Acids as Potent and Selective Inducible Nitric Oxide Synthase Inhibitors for Parkinson’s Disease

Abstract

N-Phenylpropenoyl-L-amino acids (NPAs) are inducible nitric oxide synthase (iNOS) inhibitors possessing preventive effects for Parkinson's disease (PD). Here, structural modifications for improving the iNOS inhibitory activity and blood−brain barrier (BBB) permeability of NPAs were conducted, leading to 20 optimized NPA derivatives (1−20). Compound 18, with the most potent activity (IC 50 = 74 nM), high BBB permeability (P e = 19.1 × 10 −6 cm/s), and high selectivity over other NOS isoforms, was selected as the lead compound. Further studies demonstrated that 18 directly binds to iNOS. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced acute PD model, the oral administration of 18 (1 and 2 mg/kg) exerted preventive effects by alleviating the loss of dopaminergic (DAergic) neurons. Notably, in the MPTP-/probenecid-induced chronic PD model, the same dose of 18 also displayed a therapeutic effect by repairing the damaged DAergic neurons. Finally, good pharmacokinetic properties and low toxicity made 18 a promising candidate for the treatment of PD.

Protective Effects of 4-Trifluoromethyl-(E)-cinnamoyl]-L-4-F-phenylalanine Acid against Chronic Cerebral Hypoperfusion Injury through Promoting Brain-Derived Neurotrophic Factor-Mediated Neurogenesis

“…4-Trifluoromethyl-( E )-cinnamoyl]- L -4- F -phenylalanine acid ( AE-18 ; Figure A), which was synthesized in our previous study, has been demonstrated to provide therapeutic effects in the MPTP/probenecid-induced chronic PD model through the DAergic neuronal repair pathway . In parallel, post-modeling administration of AE-18 in the midbrain ischemia-reperfusion model was also shown to reduce neurological damage, reduce infarct volume, and improve motor disturbance by increasing VEGF and BDNF levels .…”

Combination of multiple methods and views for recognition, transportation, and structure-guided modification of lysine-specific demethylase phenylcyclopropylamine inhibitor

“…Recently, 3D-QSAR modeling has been successfully applied to virtually select novel inhibitors on the basis of structure-property relationships from the ligand view. 34,35 In addition, molecular dynamics simulation has been widely employed to study the binding mode of potential inhibitors in the active site of the target for designing new compounds. 36,37 These studies provide valuable clues for drug design, while the MM MD simulations are usually used to capture static binding for the target ligand in the binding site.…”

Discovery of Coixol Derivatives as Potent Anti-inflammatory Agents

“…Compound 8 attenuated LPS-induced neuroinflammation by hindering the overexpression of NO and IL-1β . Compounds 9 and 10 functioned as iNOS inhibitors, providing relief from neuroinflammation. , Considering the anti-inflammatory capacity of coixol, we revealed two series of coixol derivatives combined with cinnamic acid and explored their anti-inflammatory activities in vitro and in vivo in this work.…”