A new series of PDGF receptor tyrosine kinase inhibitors: 3-substituted quinoline derivatives.
A series of 63 3-substituted quinoline derivatives has been prepared and tested for inhibition of cell-free platelet derived growth factor receptor tyrosine kinase (PDGF-RTK) activity. The compounds were generally prepared either by a Friedlander condensation between an aryl-acetaldehyde and an o-aminobenzaldehyde or by a palladium-catalyzed coupling between an aryl bromide or triflate and an organostannane or organozinc chloride. The presence of 6,7-dimethoxy groups on the quinoline ring was found to be advantageous although not essential for potent inhibition of PDGF-RTK. A lipophilic group attached to the quinoline 3-position contributed substantially to activity. The lipophilic groups generally consisted of monocyclic aromatics or small alkynyl, alkenyl, and alkyl groups. Optimum activity of ca. < or = 20 nM (IC50) was observed when 6,7-dimethoxyquinoline was substituted in the 3-position with 4-methoxyphenyl (15d), 3-fluoro-4-methoxyphenyl (17m), 3-fluorophenyl (17b), 4-hydroxyphenyl (24), 6-methoxypyridin-3-yl (15o), 5-pyridin-2(1H)-one (23), trans-beta-styryl (15e), thiophene-3-yl (2e), 5-chlorothiophene-2-yl (15f), or cyclopentenyl (17n) groups. Most of the compounds in the series were tested for inhibition of cell-free epidermal growth factor receptor tyrosine kinase activity and found to be inactive.
Maguire
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Rhône-Poulenc Rorer Central Research, Collegeville, Pennsylvania 19426.
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McVety
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Spada
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Zilberstein
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D016475:3T3 Cells; D000818:Animals; D051379:Mice; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D011804:Quinolines; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor