<i>N</i>-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 (<b>1-20</b>). Compound <b>18</b>, with the most potent activity (IC<sub>50</sub> = 74 nM), high BBB permeability (<i>P</i><sub>e</sub> = 19.1 × 10<sup>-6</sup> cm/s), and high selectivity over other NOS isoforms, was selected as the lead compound. Further studies demonstrated that <b>18</b> directly binds to iNOS. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced acute PD model, the oral administration of <b>18</b> (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 <b>18</b> also displayed a therapeutic effect by repairing the damaged DAergic neurons. Finally, good pharmacokinetic properties and low toxicity made <b>18</b> a promising candidate for the treatment of PD.