TY - JOUR
T1 - Hydroxyethylene isosteres of selective neuronal nitric oxide synthase inhibitors
AU - Erdal, Erik P.
AU - Martásek, Pavel
AU - Roman, Linda J.
AU - Silverman, Richard B.
N1 - Funding Information:
We are grateful to the National Institutes of Health (GM 49725 to R.B.S., and GM52419 and HL30050 to Prof. Bettie Sue Masters, in whose laboratory P.M. and L.J.R. work) for financial support of this work.
PY - 2007/9/15
Y1 - 2007/9/15
N2 - Nitric oxide (NO) is an important second messenger molecule for blood pressure homeostasis, as a neurotransmitter, and in the immune defense system. Excessive NO can lead to neurodegeneration and connective tissue damage. Three different isozymes of the enzyme nitric oxide synthase regulate NO production in endothelial (eNOS), neuronal (nNOS), and macrophage (iNOS) cells. Whereas creating a lower level of NO in some cells could be beneficial, it also could be detrimental to the protective effects that NO has on other cells. Therefore, it is essential that therapeutic NOS inhibitors be made that are subtype selective. Previously, we reported a series of nitroarginine-containing dipeptide amides as potent and selective nNOS inhibitors. Here we synthesize peptidomimetic hydroxyethylene isosteres of these dipeptide amides for potential increased bioavailability. None of the compounds is as potent or selective as the dipeptide amides, but they exhibit good inhibition and selectivity. When the terminal amino group was converted to a hydroxyl group, potency and selectivity greatly diminished, supporting the importance of the terminal amino group for binding.
AB - Nitric oxide (NO) is an important second messenger molecule for blood pressure homeostasis, as a neurotransmitter, and in the immune defense system. Excessive NO can lead to neurodegeneration and connective tissue damage. Three different isozymes of the enzyme nitric oxide synthase regulate NO production in endothelial (eNOS), neuronal (nNOS), and macrophage (iNOS) cells. Whereas creating a lower level of NO in some cells could be beneficial, it also could be detrimental to the protective effects that NO has on other cells. Therefore, it is essential that therapeutic NOS inhibitors be made that are subtype selective. Previously, we reported a series of nitroarginine-containing dipeptide amides as potent and selective nNOS inhibitors. Here we synthesize peptidomimetic hydroxyethylene isosteres of these dipeptide amides for potential increased bioavailability. None of the compounds is as potent or selective as the dipeptide amides, but they exhibit good inhibition and selectivity. When the terminal amino group was converted to a hydroxyl group, potency and selectivity greatly diminished, supporting the importance of the terminal amino group for binding.
KW - Enzyme inhibitor
KW - Hydroxyethylene isostere
KW - Nitric oxide
KW - Nitric oxide synthase
KW - nNOS inhibitor
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U2 - 10.1016/j.bmc.2007.06.038
DO - 10.1016/j.bmc.2007.06.038
M3 - Article
C2 - 17614291
AN - SCOPUS:34447642352
VL - 15
SP - 6096
EP - 6108
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 18
ER -