Description
CP 471,474 is a broad-spectrum inhibitor of matrix metalloproteinases (MMPs) with IC
50 values of 0.7, 16, 13, and 0.9 nM for MMP-2, MMP-3, MMP-9, and MMP-13, respectively. It is selective for these MMPs over MMP-1 (IC
50 = 1,170 nM). CP 471,474 reduces left ventricular enlargement and decreases the incidence of cardiac rupture in mouse models of myocardial infarction when administered at doses of 120 mg/kg twice per day and 240 mg/kg per day, respectively.
Chemical Properties
White Solid
Uses
A broad spectrum inhibitor of matrix metalloproteinases that attenuates early left ventricular dilation after experimental myocardial infarction in mice. Studies show that it also inhibits cigarette smoke-induced lung inflammation and the progression of emphysema in guinea pig models.
Biochem/physiol Actions
CP-471474 is a broad spectrum inhibitor of matrix metalloproteinases. CP-471474 has a low nM IC50 efficacy for MMP-2, MMP-3, MMP-9, and MMP-13. CP-471474 has low potency against MMP-1 (IC50 > 1 uM). CP-471474 prevents left ventricular remodeling after experimental myocardial infarction in mice. CP-471474 also inhibits cigarette smoke-induced lung inflammation and the progression of emphysema in guinea pig models.
in vivo
CP-471474 plasma levels following subcutaneous injection are 2,020 ng/mL (1 h postdose) to 160 ng/mL (6 h postdose)[2].
CP-471,474 significantly reduces both the extent and severity of inflammation at 2 months. At 4 months, a spontaneous reduction of the inflammatory response is observed in both treated and untreated animals, and consequently no difference is observed between both[2].
CP-471474 significantly decreases the destructive lesions mainly at 2 months and also at 4 months[2].
| Animal Model: | Guinea pigs weighing 400 to 450 g (COPD)[2]. |
| Dosage: | 20 mg/kg (also supplemented daily by the diet (200 mg/200 g powdered chow)). |
| Administration: | Subcutaneously (in 20% ethanol/80% polyethylene glycol), once a day during the entire course. |
| Result: | Lungs derived from smoking animals treated with the compound demonstrated a statistically significant reduction in the destructive lesions.
Showed an increase of both pro–MMP-9 and its active form (lanes 5 to 8) as compared with control animals.
|
IC 50
MMP-2: 0.7 nM (IC
50); MMP-13: 0.9 nM (IC
50); MMP-9: 13 nM (IC
50); MMP-3: 16 nM (IC
50); MMP-1: 1170 nM (IC
50)
References
[1] L E ROHDE. Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice.[J]. Circulation, 1999, 99 23: 3063-3070. DOI:
10.1161/01.cir.99.23.3063[2] LU FANG . Differences in inflammation, MMP activation and collagen damage account for gender difference in murine cardiac rupture following myocardial infarction[J]. Journal of molecular and cellular cardiology, 2007, 43 5: Pages 535-544. DOI:
10.1016/j.yjmcc.2007.06.011
