Animal experiment:

Male SHR-SPs (n=70) are randomly assigned according to body weight into five groups (n=14 per group): normal diet controls (ND), high salt-fat diet controls (SFD), SFD + GSK-AHAB (1.2 mg/kg/day), and SFD + GSK-AHAB (12 mg/kg/day) and SFD + MK 966 (18 mg/kg/day). All drugs are administered in the diet by mixing with the SFD. A subgroup of animals from each group (n=6 per group) are anesthetized and surgically instrumented with radiotelemetry units for the conscious measurement of mean arterial blood pressure and heart rate. These animals are allowed to recover for at least 7 days before the start of the study.

Losmapimod (GW856553, GW856553X, GSK-AHAB) is a potent and selective inhibitor of p38 MAPK with pKi values of 8.1 and 7.6 for p38α and p38β, respectively [1].

p38 mitogen-activated protein kinase (p38 MAPK) is an intracellular signaling kinase and plays an important role in regulating transcription and translation of the inflammatory response in macrophages and endothelial cells [2].

Losmapimod is an orally active p38 MAPK inhibitor. In the spontaneously hypertensive stroke-prone rats (SHR-SPs) with a salt-fat diet, GSK-AHAB significantly improved survival and renal function in a dose-dependent way and induced vascular relaxation. Also, GSK-AHAB attenuated hypertension, cardiac remodeling, dyslipidemia, plasma renin activity (PRA), interleukin-1
(IL-1
) and aldosterone [1]. In patients with hypercholesterolemia, losmapimod improved acetylcholine, sodium nitroprusside and NG-monomethyl-L-arginine (L-NMMA) responses by 25%, 20% and 10%, respectively. Also, losmapimod reduced C-reactive protein (a systemic inflammatory marker) by 57%. These results suggested that losmapimod improved NO-mediated vasodilatation and inhibited inflammation [2]. In patients with chronic obstructive pulmonary disease (COPD), losmapimod (7.5 mg twice daily) reduced plasma fibrinogen by 11% and was well tolerated [3].

References:
[1].  Willette RN, Eybye ME, Olzinski AR, et al. Differential effects of p38 mitogen-activated protein kinase and cyclooxygenase 2 inhibitors in a model of cardiovascular disease. J Pharmacol Exp Ther, 2009, 330(3): 964-970.
[2].  Cheriyan J, Webb AJ, Sarov-Blat L, et al. Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation., 2011, 123(5): 515-523.
[3].  Lomas DA, Lipson DA, Miller BE, et al. An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol, 2012, 52(3): 416-424.