Nitric oxide synthase (NOS) is a family of enzymes that produces nitric oxide for use in regulating blood pressure, in immune system functioning, and in brain development, memory, and learning. Under pathological conditions, excess nitric oxide is produced, which can result in damage to tissues, leading to neurodegenerative diseases. The broad objective of inhibition of neuronal nitric oxide synthase is the development of a treatment for neurodegeneration in Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, and cerebral palsy. Selective inhibition of the neuronal isozyme of NOS is important to prevent hypertension and interference with the immune defense system.
The specific aims for the next budget period have been streamlined from the seven proposed in the last version of this proposal to five, which emphasize the design, synthesis, potency, and bioavailability of enhanced nNOS-selective inhibitors. Approaches will be presented to increase potency, selectivity, and their ability to cross the blood-brain barrier. The first specific aim, however, focuses on a mechanistic question related to a class of NOS inactivators. The five areas of proposed research are as follows: (1) Studies will be carried out on the mechanisms of inactivation of nitric oxide synthase by amidine and substituted arginine inactivators. (2) Structure-based de novo design of analogues of our most potent and selective new series of compounds obtained from computer modeling will be carried out and synthesized. (3) Selective nNOS inhibitors for human nNOS will be designed based on homology modeling of human nNOS into the crystal structure of rat nNOS and on site-directed mutagenesis of a key residue difference in rat versus human nNOS. The homology model will be supported by inhibition studies using human and lower animal nitric oxide synthases. Attempts at obtaining a crystal structure of human nitric oxide synthases are being made by a collaborator. (4) Novel subunit dimerization inhibitors of neuronal nitric oxide synthase will be designed and synthesized. (5) Various bioavailability studies will be carried out, including in vivo studies to determine if our selective inhibitors cross the blood-brain barrier;stability studies of the compounds with microsomes;Caco-2 cell permeability studies;substrate activity studies for the P-glycoprotein efflux transporter. Prodrug analogues will be synthesized to increase bioavailability.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM049725-15
Application #
7783840
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
1994-04-01
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
15
Fiscal Year
2010
Total Cost
$287,768
Indirect Cost
Name
Northwestern University at Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Cinelli, Maris A; Li, Huiying; Chreifi, Georges et al. (2017) Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors. J Med Chem 60:3958-3978
Pensa, Anthony V; Cinelli, Maris A; Li, Huiying et al. (2017) Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors. J Med Chem 60:7146-7165
Do, Ha T; Wang, Heng-Yen; Li, Huiying et al. (2017) Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker. J Med Chem 60:9360-9375
Wang, Heng-Yen; Qin, Yajuan; Li, Huiying et al. (2016) Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker. J Med Chem 59:4913-25
Cinelli, Maris A; Li, Huiying; Pensa, Anthony V et al. (2016) Correction to Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase. J Med Chem 59:1246
Li, Huiying; Wang, Heng-Yen; Kang, Soosung et al. (2016) Electrostatic Control of Isoform Selective Inhibitor Binding in Nitric Oxide Synthase. Biochemistry 55:3702-7
Holden, Jeffrey K; Lewis, Matthew C; Cinelli, Maris A et al. (2016) Targeting Bacterial Nitric Oxide Synthase with Aminoquinoline-Based Inhibitors. Biochemistry 55:5587-5594
Mukherjee, Paramita; Li, Huiying; Sevrioukova, Irina et al. (2015) Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase. J Med Chem 58:1067-88
Kang, Soosung; Li, Huiying; Tang, Wei et al. (2015) 2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity. J Med Chem 58:5548-60
Holden, Jeffrey K; Kang, Soosung; Hollingsworth, Scott A et al. (2015) Structure-based design of bacterial nitric oxide synthase inhibitors. J Med Chem 58:994-1004

Showing the most recent 10 out of 96 publications