Optimization of Blood–Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2‑Aminopyridine Scaffold

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.