期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 5, 页码 2690-2707出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b02032
关键词
-
资金
- National Institutes of Health [R01 GM049725, GM057353]
- Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource [NSF NNCI-1542205]
- State of Illinois
- International Institute for Nanotechnology (IIN)
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 pK(a) 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-i < 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据