title: Restenosis following angioplasty in the swine coronary artery is inhibited by an orally active PDGF-receptor tyrosine kinase inhibitor, RPR101511A.
abstract: BACKGROUND
  Platelet-derived growth factor (PDGF), a purported mediator of arterial response to injury, stimulates proliferation, chemotaxis, and matrix production by activation of its membrane receptor tyrosine kinase. Because these activities underlie restenosis, inhibition of the PDGF-receptor tyrosine kinase (PDGFr-TK) is postulated to decrease restenosis.
  
  
  RESULTS
  RPR101511A is a novel compound which selectively and potently inhibits the cell-free and in situ PDGFr-TK and PDGFr-dependent proliferation and chemotaxis in vascular smooth muscle cells (VSMC). To evaluate the effect of RPR101511A (30 mg. kg-1. d-1 BID for 28 days following PTCA) on coronary restenosis, PTCA was performed in hypercholesterolemic minipigs whose left anterior descending (LAD) coronary artery had been injured by overdilation and denudation, yielding a previously existing lesion. Angiographically determined prePTCA minimal lumen diameters (MLD) were similar in vehicle and RPR101511A-treated pigs (1.98+/-0.09 versus 2.01+/-0.08 mm) and increased to the same extent in the 2 groups following successful PTCA (2.30+/-0.06 versus 2.52+/-0.13). At termination, there was an average 50% loss of gain in the vehicle-treated group but no loss of gain with RPR101511A (2.16+/-0. 05 versus 2.59+/-0.11, P<0.001). Morphometric analysis of the LAD showed that RPR101511A caused a significant decrease in total intimal/medial ratio (0.96+/-0.58 versus 0.67+/-0.09, P<0.05).
  
  
  CONCLUSIONS
  RPR101511A, which acts by inhibition of the PDGFr-TK, completely prevented angiographic loss of gain following PTCA and significantly reduced histological intimal hyperplasia.
authors.affiliation: Department of Cardiovascular Biology, Medicinal Chemistry, Rhone-Poulenc Rorer, Collegeville, PA, USA. Glenda.BILDER@RPRorer.com
authors.forename: G
authors.initials: G
authors.lastname: Bilder
authors.forename: T
authors.initials: T
authors.lastname: Wentz
authors.forename: R
authors.initials: R
authors.lastname: Leadley
authors.forename: D
authors.initials: D
authors.lastname: Amin
authors.forename: L
authors.initials: L
authors.lastname: Byan
authors.forename: B
authors.initials: B
authors.lastname: O'Conner
authors.forename: S
authors.initials: S
authors.lastname: Needle
authors.forename: H
authors.initials: H
authors.lastname: Galczenski
authors.forename: J
authors.initials: J
authors.lastname: Bostwick
authors.forename: C
authors.initials: C
authors.lastname: Kasiewski
authors.forename: M
authors.initials: M
authors.lastname: Myers
authors.forename: A
authors.initials: A
authors.lastname: Spada
authors.forename: L
authors.initials: L
authors.lastname: Merkel
authors.forename: C
authors.initials: C
authors.lastname: Ly
authors.forename: P
authors.initials: P
authors.lastname: Persons
authors.forename: K
authors.initials: K
authors.lastname: Page
authors.forename: M
authors.initials: M
authors.lastname: Perrone
authors.forename: C
authors.initials: C
authors.lastname: Dunwiddie
mesh_terms: D000284:Administration, Oral; D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D003327:Coronary Disease / Q000517:prevention & control* / Q000628:therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011810:Quinoxalines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D012008:Recurrence; D013552:Swine; D013876:Thiophenes / Q000494:pharmacology*; D013997:Time Factors; D017539:Tunica Intima / Q000378:metabolism; D017540:Tunica Media / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011810:Quinoxalines; C120004:RPR 101511A; D013876:Thiophenes; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor