Nitric oxide synthases (NOS) are a family of enzymes that catalyse the formation of NO. The family of NOSs consists constitutive isoforms, neuronal NOS (nNOS) and endothelial NOS (eNOS), and a calcium-independent, inducible NOS (iNOS). NO is an important physiological mediator that plays a role in the regulation of blood pressure and blood flow. Moreover, NO acts as a neurotransmitter in the central and peripheral systems and in the immune system. GW274150 is a selective, long acting and orally active iNOS inhibitor.
GW274150 is a potent, time-dependent, highly selective inhibitor of human iNOS vs eNOS (>100-fold) or nNOS (>80-fold). In particular, GW274150 is an arginine competitive, NADPH-dependent inhibitors of human iNOS with steady-state Kd values of <40 and <90 nM, respectively. Furthermore, GW274150 inhibits 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. Thus, GW274150 is competitive with L-arginine for binding to human inducible NOS. In contrast, GW274150 is a very weak inhibitor of eNOS in aortic rings and of nNOS in cortical slices. As a result, GW274150 is a potent, highly selective iNOS inhibitor in cells and tissues.
In vivo, GW274150 is a low potency inhibitor of nNOS in the rat cerebellum with no significant effects observed at doses up to 50 mg/kg (13±14% inhibition). Higher doses of GW274150 do cause significant inhibition: 47±5% inhibition at 100 mg/kg, 63±4% inhibition at 200 mg/kg (n=5 per group).
All in all, GW274150 is a highly selective, time-dependent inhibitor of isolated iNOS vs eNOS or nNOS.