3,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase (nNOS) inhibitors.
A series of 3,5-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). Various guanidine isosteric groups were explored at the 5-position of the indole ring, while keeping the basic amine side chain such as N-methylpiperidine ring, fixed at the 3-position of the indole ring. Compounds having 2-thiophene amidine and 2-furanyl amidine groups (7, 8, 10 and 12) showed increased activity for human neuronal NOS and good selectivity over endothelial and inducible NOS isoforms. Compound 8 was shown to reverse (10mg/kg, ip) thermal hyperalgesia in the L(5)/L(6) spinal nerve ligation (neuropathic pain) model and was devoid of any significant drug-drug interaction potential due to cytochrome P450 inhibition or cardiovascular liabilities associated with the inhibition of endothelial NOS.
NeurAxon Inc., 2395 Speakman Drive, Suite #1001, Mississauga, ON, Canada L5K 1B3. sannedi@neuraxon.com
Subhash C
SC
Annedi
Shawn P
SP
Maddaford
Jailall
J
Ramnauth
Paul
P
Renton
Joanne
J
Speed
Suman
S
Rakhit
John S
JS
Andrews
Frank
F
Porreca
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D008881:Migraine Disorders / Q000188:drug therapy; D009437:Neuralgia / Q000188:drug therapy*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D013127:Spinal Nerves / Q000187:drug effects*
D065607:Cytochrome P-450 Enzyme Inhibitors; D007211:Indoles; D003577:Cytochrome P-450 Enzyme System; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III