1296310-72-9Relevant academic research and scientific papers
POTENT HUMAN NEURONAL NITRIC OXIDE SYNTHASE INHIBITORS
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Paragraph 00377; 00379, (2021/09/04)
Disclosed are 2-aminopyridine derivative compounds for use as inhibitors of nitric oxide synthase (NOS). In particular, the field of the invention relates to 2-aminopyridine derivative compounds for use as inhibitors of neuronal nitric oxide synthase (nNOS), which are formulated as pharmaceutical compositions for treating diseases and disorders associated with nNOS such as Alzheimer's, Parkinson's, and Huntington's diseases, and amytrophic lateral sclerosis, cerebral palsy, stroke/ischemic brain damage, and migraine headaches.
Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold
Do, Ha T.,Li, Huiying,Chreifi, Georges,Poulos, Thomas L.,Silverman, Richard B.
supporting information, p. 2690 - 2707 (2019/03/11)
Effective delivery of therapeutic drugs into the human brain is one of the most challenging tasks in central nervous system drug development because of the blood-brain barrier (BBB). To overcome the BBB, both passive permeability and efflux transporter liability of a compound must be addressed. Herein, we report our optimization related to BBB penetration of neuronal nitric oxide synthase (nNOS) inhibitors toward the development of new drugs for neurodegenerative diseases. Various approaches, including enhancing lipophilicity and rigidity of new inhibitors and modulating the pKa of amino groups, have been employed. In addition to determining inhibitor potency and selectivity, crystal structures of most newly designed compounds complexed to various nitric oxide synthase isoforms have been determined. We have discovered a new analogue (21), which exhibits not only excellent potency (Ki 30 nM) in nNOS inhibition but also a significantly low P-glycoprotein and breast-cancer-resistant protein substrate liability as indicated by an efflux ratio of 0.8 in the Caco-2 bidirectional assay.
