Effect of potential amine prodrugs of selective neuronal nitric oxide synthase inhibitors on blood–brain barrier penetration

Abstract

Several prodrug approaches were taken to mask amino groups in two potent and selective neuronal nitric oxide synthase (nNOS) inhibitors containing either a primary or secondary amino group to lower the charge and improve blood-brain barrier (BBB) penetration. The primary amine was masked as an azide and the secondary amine as an amide or carbamate. The azide was not reduced to the amine under a variety of in vitro and ex vivo conditions. Despite the decrease in charge of the amino group as an amide and as carbamates, BBB penetration did not increase. It appears that the use of azides as prodrugs for primary amines or amides and carbamates as prodrugs for secondary amines are not universally effective approaches for CNS applications.Keywords amine prodrug; neuronal nitric oxide synthase inhibitor; blood-brain barrier; organic azide

Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker

“…17 These inhibitors, however, still suffer from low membrane permeability and poor ability to cross the BBB as a result of their high basicity and/or polarity. In the past few years our group has pursued various medicinal chemistry approaches to improve the pharmacokinetic values of nNOS inhibitors, such as incorporating intramolecular hydrogen bonds ( 1 ), 18 converting to prodrugs ( 2 ), 19 modulating the amine basicity ( 3 ), 20 and replacing an essential pharmacophore, such as replacement of the 2-aminopyridine with a 2-imidazolylpyrimidine ( 4 ) 21 or 2-aminoquinoline ( 5 ) 22 (Figure 1). Although some pharmacokinetic improvement has been achieved, these approaches can result in a diminution in activity, especially for human nNOS, the ultimate target for neurodegenerative diseases, and in the selectivity over human eNOS.…”

Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain

“…Numerous studies were undertaken in attempt to improve the membrane permeation and bioavailability of pyrrolidinomethyl-2-aminopyridines, including alkyl chain fluorination, 115,116 the introduction of internal hydrogen-bonding groups, 117 lipophilic moieties and aromatic tails, 118 alkylation and conformational restriction, 119 the introduction of various prodrug moieties and the use of azides as amine surrogates, 120 replacement of the aminopyridine with a less basic aminothiazole, 121 and the replacement of amino linkages with amides and ethers. 108,122 Most of these approaches were met with diminished activity and selectivity relative to the parent compounds, were synthetically challenging, or did not improve BBB permeation.…”

Neuronal Nitric Oxide Synthase Inhibition Prevents Cerebral Palsy following Hypoxia-Ischemia in Fetal Rabbits: Comparison between JI-8 and 7-Nitroindazole

“…A new series of nNOS inhibitors was designed using fragment hopping [Ji et al, 2008[Ji et al, , 2009bSilverman et al, 2009], a new fragment-based approach, for de novo in- 1575 mol/kg of JI-8 (to n = 9 dams) or 7-NI (n = 5) or equivolume saline (n = 8) were given before and after HI. 7-NI significantly decreased the heart rate (HR) at multiple time points, while JI-8 had no effect.…”