Synthesis and Evaluation of Dipeptide Amides Containing N^ω-Nitroarginine and D-2, 4-Diaminobutyric Acids as Inhibitors of Neuronal Nitric Oxide Synthase

Abstract

Selective inhibition of the isoforms of nitric oxide synthase (NOS) could be beneficial in the treatment of certain disease states arising from the overproduction of nitric oxide by NOS. Recently, we reported dipeptide amides containing a basic amine side chain as potent and selective inhibitors of neuronal NOS (Huang, H. et al. (1999) J. Med. Chem., 42, 3147). The most potent nNOS inhibitor among these compounds is L-Arg^NO₂-L-Dbu-NH₂ (1) (K_i = 130nM), which also exhibits the highest selectivity over eNOS (> 1500-fold). The D,D-dipeptide, D-Lys-D-Arg^NO₂-NH₂ (3) also shows high potency and selectivity. Here the dipeptide amides containing Arg^NO₂ and D-Dbu (9–12) were synthesized and evaluated. They are all modest inhibitors of nNOS, but poor inhibitors of eNOS and iNOS. D-Dbu-D-Arg^NO₂-NH₂ (12) exhibits decreased inhibitory potency as compared with 3. A hypothesis regarding the binding at the active site of nNOS is proposed to explain the potency differences between the L- and D-form dipeptide amides.

Key Words:

• Dipeptide amide
• Nitric oxide synthase
• Nitroarginine
• D-2, 4-Diaminobutyric acid
• Enzyme inhibition