6NHE

Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-(5-(2-((2S,4R)-4-ethoxy-1-methylpyrrolidin-2-yl)ethyl)-2,3-difluorophenethyl)-4-methylpyridin-2-amine

Summary for 6NHE

• Entry DOI: 10.2210/pdb6nhe/pdb
• Descriptor: Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (7 entities in total)
• Functional Keywords: nitric oxide synthase inhibitor complex heme enzyme, oxidoreductase
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 2
• Total formula weight: 100331.04

Authors

Li, H.,Poulos, T.L. (deposition date: 2018-12-21, release date: 2019-03-13, Last modification date: 2023-10-11)

Primary citation

Do, H.T.,Li, H.,Chreifi, G.,Poulos, T.L.,Silverman, R.B.
Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold.
J. Med. Chem., 62:2690-2707, 2019

PubMed Abstract: 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 p K 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 ( K < 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.

PubMed: 30802056
DOI: 10.1021/acs.jmedchem.8b02032

Experimental method

X-RAY DIFFRACTION (1.999 Å)