SKI2852

SKI2852 is a potent, selective and orally active 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor with IC₅₀s of 1.6 nM and 2.9 nM against mHSD1 and hHSD1, respectively^[1]. IC50 & Target:IC50: 1.6 nM (mHSD1), 2.9 nM (hHSD1)^[1] In Vitro:SKI2852 inhibits 11β-HSD1 with an IC₅₀ of 4.4 ± 0.5 nM in HEK293 cells stably transfected with human 11β-HSD1 cDNA^[1].
The amide carbonyl group of SKI2852 established a central hydrogen bond interaction with the hydroxyl side chain of Ser170, one of the key residues (Ser170, Tyr183, and Lys 187) that define the catalytic triad for 11β-HSD1 activity^[1]. In Vivo:SKI2852 (20 mg/kg; oral; once daily for 25 days) significantly reduces blood glucose and HbA1c levels and improved the lipid profiles in ob/ob mice^[1].
In Vivo PK Data for SKI2852^[1]

species	iva				pob
	CL (L/kg/h)	Vss (L/kg)	t1/2 (h)	AUC (μg × h/mL)	Cmax (μg/mL)	tmax (h)	AUC (μg × h/mL)	F (%)
mousec	0.42	1.1	1.7	2.35	2.21	1.0	11.26	96
ratc	0.93	2.1	1.8	1.12	1.02	1.3	3.39	60
dogd	0.36	2.4	4.7	1.47	1.12	2.1	11.52	98

^a10% hydroxylpropyl-β-cyclodextrin was used as vehicle. ^b0.5% methylcellulose and 1% Tween80 was used as vehicle. ^cDosed iv at 1 mg/kg, po at 5mg/kg. ^dDosed iv at 0.5 mg/kg, po at 4 mg/kg.