Analogues of 2-aminopyridine-based selective inhibitors of neuronal nitric oxide synthase with increased bioavailability.
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.
Lawton
Graham R
GR
Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA.
Ralay Ranaivo
Hantamalala
H
Chico
Laura K
LK
Ji
Haitao
H
Xue
Fengtian
F
Martásek
Pavel
P
Roman
Linda J
LJ
Watterson
D Martin
DM
Silverman
Richard B
RB
D000478:Alkylation; D000586:Amination; D000631:Aminopyridines / Q000737:chemistry*; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization
D000631:Aminopyridines; D004791:Enzyme Inhibitors; D052248:Nitric Oxide Synthase Type I; C032439:alpha-aminopyridine