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 (IC50 = 74 nM), high BBB permeability (Pe = 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.

• Authors: Xiao-Long Hu, Xian-Yu Lv, Rong Wang, Huan Long, Jia-Hao Feng, Bao-Lin Wang, Wei Shen, Hao Liu, Fei Xiong, Xiao-Qi Zhang, Wen-Cai Ye, Hao Wang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 11 Pg. 7760-7777 (06 10 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34019417 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Isoenzymes
• Propanols
• 1-phenylpropanol
• Nitric Oxide
• Nitric Oxide Synthase Type II

Topics

• Amino Acids (chemistry, metabolism, pharmacology)
• Animals
• Binding Sites
• Blood-Brain Barrier (drug effects, metabolism)
• Disease Models, Animal
• Dopaminergic Neurons (drug effects, metabolism)
• Drug Design
• Half-Life
• Humans
• Isoenzymes (antagonists & inhibitors, metabolism)
• MPTP Poisoning (drug therapy, pathology)
• Maze Learning (drug effects)
• Mice
• Mice, Inbred C57BL
• Microglia (cytology, drug effects, metabolism)
• Molecular Docking Simulation
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (antagonists & inhibitors, metabolism)
• Propanols (chemistry)
• Structure-Activity Relationship