GW274150 and GW273629 are potent and highly selective inhibitors of inducible nitric oxide synthase in vitro and in vivo
WK Alderton, ADR Angell, C Craig… - British journal of …, 2005 - Wiley Online Library
WK Alderton, ADR Angell, C Craig, J Dawson, E Garvey, S Moncada, J Monkhouse, D Rees…
British journal of pharmacology, 2005•Wiley Online Library1 GW274150 ([2‐[(1‐iminoethyl) amino] ethyl]‐l‐homocysteine) and GW273629 (3‐[[2‐[(1‐
iminoethyl) amino] ethyl] sulphonyl]‐l‐alanine) are potent, time‐dependent, highly selective
inhibitors of human inducible nitric oxide synthase (iNOS) vs endothelial NOS (eNOS)(> 100‐
fold) or neuronal NOS (nNOS)(> 80‐fold). GW274150 and GW273629 are arginine
competitive, NADPH‐dependent inhibitors of human iNOS with steady state Kd values of<
40 and< 90 nm, respectively. 2 GW274150 and GW273629 inhibited intracellular iNOS in …
iminoethyl) amino] ethyl] sulphonyl]‐l‐alanine) are potent, time‐dependent, highly selective
inhibitors of human inducible nitric oxide synthase (iNOS) vs endothelial NOS (eNOS)(> 100‐
fold) or neuronal NOS (nNOS)(> 80‐fold). GW274150 and GW273629 are arginine
competitive, NADPH‐dependent inhibitors of human iNOS with steady state Kd values of<
40 and< 90 nm, respectively. 2 GW274150 and GW273629 inhibited intracellular iNOS in …
- 1GW274150 ([2‐[(1‐iminoethyl) amino]ethyl]‐L‐homocysteine) and GW273629 (3‐[[2‐[(1‐iminoethyl)amino]ethyl]sulphonyl]‐L‐alanine) are potent, time‐dependent, highly selective inhibitors of human inducible nitric oxide synthase (iNOS) vs endothelial NOS (eNOS) (>100‐fold) or neuronal NOS (nNOS) (>80‐fold). GW274150 and GW273629 are arginine competitive, NADPH‐dependent inhibitors of human iNOS with steady state Kd values of <40 and <90 nM, respectively.
- 2GW274150 and GW273629 inhibited intracellular iNOS in J774 cells in a time‐dependent manner, reaching IC50 values of 0.2±0.04 and 1.3±0.16 μM, respectively. They were also acutely selective in intact rat tissues: GW274150 was >260‐fold and 219‐fold selective for iNOS against eNOS and nNOS, respectively, while GW273629 was >150‐fold and 365‐fold selective for iNOS against eNOS and nNOS, respectively.
- 3The pharmacokinetic profile of GW274150 was biphasic in healthy rats and mice with a terminal half‐life of ∼6 h. That of GW273629 was also biphasic in rats, producing a terminal half‐life of ∼3 h. In mice however, elimination of GW273629 appeared monophasic and more rapid (∼10 min). Both compounds show a high oral bioavailability (>90%) in rats and mice.
- 4GW274150 was effective in inhibiting LPS‐induced plasma NOx levels in mice with an ED50 of 3.2±0.7 mg kg−1 after 14 h intraperitoneally (i.p.) and 3.8±1.5 mg kg−1 after 14 h when administered orally. GW273629 showed shorter‐lived effects on plasma NOx and an ED50 of 9±2 mg kg−1 after 2 h when administered i.p.
- 5The effects of GW274150 and GW273629 in vivo were consistent with high selectivity for iNOS, as these inhibitors were of low potency against nNOS in the rat cerebellum and did not cause significant effects on blood pressure in instrumented mice.
British Journal of Pharmacology (2005) 145, 301–312. doi:10.1038/sj.bjp.0706168
Wiley Online Library