Abstract
Under different pathological conditions, aberrant induction of neuronal nitric oxide synthase (nNOS) generates overproduction of NO that can cause irreversible cell damage. The aim of this study was to develop an amidoxime prodrug of a potent nNOS inhibitor, the benzhydryl acetamidine. We synthesized the benzhydryl acetamidoxime, which was evaluated in vitro to ascertain the potential NOS inhibitory activity, as well as conducting bioconversion into the parent acetamidine. The prodrug was also profiled for in vitro physicochemical properties, by determining the lipophilicity, passive permeation through the human gastrointestinal tract and across the blood‐brain barrier by PAMPA, and chemical, enzymatic, and plasma stability. The obtained data demonstrate that the amidoxime prodrug shows an improved pharmacokinetic profile with respect to the acetamidine nNOS inhibitor, thus suggesting that it could be a promising lead compound to treat all those pathological conditions in which nNOS activity is dysregulated.
Highlights
Introduction are constitutive and calcium dependent„ and catalyze the production of low and pulsating Nitric oxide (NO) levels
ENOS is mainly expressed in endothelial cells, and plays a pivotal role in the control of blood pressure, platelet aggregation, atherosclerosis and angiogenesis.[6,7] neuronal nitric oxide synthase (NOS) (nNOS) is localized in neurons, in epithelial cells of various organs, and in the skeletal muscle
In order to optimize the pharmacokinetic properties of the nNOS inhibitor 1, in this study we present the synthesis of amidoxime prodrug 2 (Figure 1), which was in vitro evaluated to ascertain the potential NOS inhibitory activity, as well as its bioconversion into the acetamidine 1 by mitochondrial amidoxime reducing component (mARC).[38]
Summary
Introduction are constitutive and calcium dependent„ and catalyze the production of low and pulsating NO levels. ENOS is mainly expressed in endothelial cells, and plays a pivotal role in the control of blood pressure, platelet aggregation, atherosclerosis and angiogenesis.[6,7] nNOS is localized in neurons, in epithelial cells of various organs, and in the skeletal muscle This isozyme has a role in the regulation of neurotransmission, synaptic plasticity, and neural development as well as in the relaxation of nonvascular smooth muscle, and in the cardiovascular function.[8] Unlike the other two isoforms, the expression of iNOS can be induced in different cell types in response to pro-inflammatory stimuli, such as cytokines, bacterial lipopolysaccharides or other inflammatory agents.[9]. There are three distinct isoforms of NOS: the endothelial NOS (eNOS) and neuronal NOS (nNOS)
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