GW274150 is a Selective, Long Acting and Orally Active iNOS Inhibitor

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.

Alderton WK, et al. GW274150 and GW273629 are potent and highly selective inhibitors of inducible nitric oxide synthase in vitro and in vivo. Br J Pharmacol. 2005 Jun;145(3):301-12.