Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping
Selective inhibition of neuronal nitric oxide synthase (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. This study shows that not only greater inhibitory potency and isozyme selectivity but more druglike properties can be achieved by fragment hopping. On the basis of the structure of lead molecule 6, fragment hopping effectively extracted the minimal pharmacophoric elements in the active site of nNOS for ligand hydrophobic and steric interactions and generated appropriate lipophilic fragments for lead optimization. More potent and selective inhibitors with better druglike properties were obtained within the design of 20 derivatives (compounds 7-26). Our structure - based inhibitor design for nNOS and SAR analysis reveal the robustness and efficiency of fragment hopping in lead discovery and structural optimization, which implicates a broad application of this approach to many other therapeutic targets for which known druglike small-molecule modulators are still limited.
Ji, Haitao,Li, Huiying,Martásek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
supporting information; experimental part
p. 779 - 797
(2009/12/07)
POTENT AND HIGHLY SELECTIVE HETEROAROMATIC INHIBITORS OF NEURONAL NITRIC OXIDE SYNTHASE
Peptidomimetic compounds as can inhibit neuronal nitric oxide synthase (nNOS) for potential treatment in neurodegenerative diseases, such as but not limited to stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease.
-
(2008/06/13)
NOS INHIBITORS FOR TREATMENT OF MOTOR DEFICIT DISORDERS
The present invention relates to preventive therapies and treatments of motor deficit disorders. In particular, the present invention relates to compositions and methods for preventative therapy and treatment of motor deficit disorders, such as cerebral p
-
Page/Page column 4; 5/8
(2008/06/13)
More Articles about upstream products of 1018909-16-4