Optimization of <i>N</i>-Phenylpropenoyl-l-amino Acids as Potent and Selective Inducible Nitric Oxide Synthase Inhibitors for Parkinson's Disease.

ID: ALA5046219

Journal: J Med Chem

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

Authors: Hu XL, Lv XY, Wang R, Long H, Feng JH, Wang BL, Shen W, Liu H, Xiong F, Zhang XQ, Ye WC, Wang H.

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 (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.

CiteXplore: 34019417

DOI: 10.1021/acs.jmedchem.1c00578

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