Inhibition of PDGF receptor binding and PDGF-stimulated biological activity in vitro and of intimal lesion formation in vivo by 2-bromomethyl-5-chlorobenzene sulfonylphthalimide.
The proliferation of vascular smooth muscle cells (SMCs) is a key event in the development of atherosclerotic lesions and in the restenosis of arteries after angioplasty. Polypeptide growth factors are potent SMC mitogens in vitro and are believed to be involved in SMC proliferation in vivo. Strong data exist linking platelet-derived growth factor (PDGF) activity to human atherosclerosis. However, no low-molecular-weight antagonists of this growth factor have been discovered. We identified a compound, SCH 13929 (2-bromomethyl-5-chlorobenzene sulfonylphthalimide), which inhibits binding of 125I-PDGF BB to cell surface receptors with an IC50 of 0.13 mumol/L. This compound has a lesser effect on the binding of 125I-epidermal growth factor (EGF), 125I-basic fibroblast growth factor (bFGF), or 125I-endothelin to specific cell surface receptors. Exposure of cultured SMCs to SCH 13929 inhibits PDGF BB- and PDGF AA-stimulated DNA synthesis but not EGF- or bFGF-stimulated DNA synthesis. PDGF BB-stimulated SMC division is also inhibited by exposure to SCH 13929. Chemotaxis assays indicate that SCH 13929 inhibits PDGF-stimulated directional migration and suggest that the compound interacts with PDGF rather than with the receptor. Oral administration of SCH 13929 (100 mg/kg per day) to Sprague-Dawley rats or spontaneously hypertensive rats results in significant inhibition of lesion formation in the balloon catheter-deendothelialized carotid artery. These results suggest that SCH 13929 may be a useful tool for understanding the role of PDGF in intimal lesion formation.
Schering-Plough Research Institute, Kenilworth, NJ 07033-0539.
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DE
Mullins
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F
Hamud
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R
Reim
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HR
Davis
D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D002417:Cattle; D002455:Cell Division; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002722:Chlorobenzenes / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010797:Phthalimides / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology
D002722:Chlorobenzenes; D006133:Growth Substances; D010797:Phthalimides; D010982:Platelet-Derived Growth Factor; C088156:2-bromomethyl-5-chlorobenzene sulfonylphthalimide; D004247:DNA; D017479:Receptors, Platelet-Derived Growth Factor