Abstract
Overproduction of nitric oxide by neuronal nitric oxide synthase (nNOS) has been linked to several neurodegenerative diseases. We have recently designed potent and isoform selective inhibitors of nNOS, but the lead compound contains several basic functional groups. A large number of charges and hydrogen bond donors can impede the ability of molecules to cross the blood brain barrier and thereby limit the effectiveness of potential neurological therapeutics. Replacement of secondary amines in our lead compound with neutral ether and amide groups was made to increase bioavailability and to determine if the potency and selectivity of the inhibitor would be impacted. An ether analogue has been identified that retains a similar potency and selectivity to that of the lead compound, and shows increased ability to penetrate the blood brain barrier.
Original language | English (US) |
---|---|
Pages (from-to) | 2371-2380 |
Number of pages | 10 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 17 |
Issue number | 6 |
DOIs | |
State | Published - Mar 15 2009 |
Funding
The authors are grateful to the National Institutes of Health for financial support to R.B.S. (GM49725) and Dr. Bettie Sue Masters (GM52419, with whose laboratory P.M. and L.J.R. are affiliated), as well as the Robert A. Welch Foundation to Dr. Bettie Sue Masters (AQ1192). P.M. is supported by Grants 0021620806 and 1M0520 from MSMT of the Czech Republic. The authors wish to thank Dr. Michael Avram and Lynn Luong of the Northwestern Clinical Pharmacology Core Facility and the Pharmaceutical Chemistry Translational Resource of the Center for Drug Discovery and Chemical Biology for carrying out the SPE and LCMS experiments.
Keywords
- Aminopyridine
- Bioavailability
- Blood-brain barrier
- Ether
- Neuronal nitric oxide synthase
- Neuronal nitric oxide synthase inhibitors
ASJC Scopus subject areas
- Drug Discovery
- Molecular Medicine
- Molecular Biology
- Biochemistry
- Clinical Biochemistry
- Pharmaceutical Science
- Organic Chemistry