BMS-582949

BMS-582949 (compound 7k) is an orally active and highly selective p38α MAP kinase inhibitor, with IC₅₀ values of 13 nM for p38α, and 50 nM for cellular TNFα. BMS-582949 can be used for research on rheumatoid arthritis^[1]. In Vivo:BMS-582949 (5 mg/kg, p.o., 90 min) reduces the LPS induced TNFα production significantly in murine models of acute inflammation from BALB/c female mice^[1].
BMS-582949 (0.3-100 mg/kg, p.o., q.d/b.i.d) reduces paw swelling significantly^[1].
BMS-582949 intravenous injection (i.v.) dissolution protocol uses 25% NMP, 33% PEG 400, 9% PG, and 33% water as a vehicle^[1].
BMS-582949 oral gavage (p.o.) dissolution protocol uses PEG 400 as a vehicle^[1].

Pharmacokinetic Properties of Compound 7k in Mice and Rats^[1]

Compound 7k 在小鼠和大鼠中的药代动力学分析^[1]

	mouse	rat
%Fpo	90	60
Cmax(μM)	15.3	7.0
Tmax(h)	1.0	1.5
T1/2(h)	2.6	4.0
MRT (h)	3.3	3.4
CL (mL/min/kg)	4.4	5.4
Vss(L/kg)	0.9	1.1
AUC0-8 h(μM•h)	75.5
AUC0-24 h(μM•h)		45.4

In Vitro Profile of 7k^[1]

体外代谢分析^[1]

profiling assays	results
liver microsome metabolic rate (nmol/min/mg)	mouse: 0.011 rat: 0.008 human: 0.013
hepatocyte metabolic rate (nmol/min/million cells)	mouse: 0.006 rat: 0.015 human: 0.015
P450 IC50(μM)	>40 for 1A2, 2C9 2C19, and 2D6 18-40 for 3A4
Caco-2 permeability (nm/s)	121-134
serum protein binding (%)	mouse: 86.3 rat: 89.7 human: 81.5
Ames	negative in T98 and T100±S9 activation
SOS chromotest	negative
HHA IC50(μM)	>138
hERG inhibition	16% at 30 μM
kinase selectivity	>2000 fold over 57 diverse kinase 450 fold over Jnk2 190 fold over Raf 5 fold over p38α