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 arylacetaldehyde 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. 120 nM (ICm) 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-methoxypyridin3-y1(150), B-pyridin-2(1H)-one (23), trans-@-styryl(15e), thiophene-3-y1(2e), 5-chlorothiophene2-yl (150, or cyclopentenyl (17x1) 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. Platelet-derived growth factor (PDGF) receptors are integral, transmembrane glycoproteins whose expression is generally limited to cells of mesodermal 0rigin.l Abnormal expression of PDGF and/or PDGF receptors has been linked to a number of pathophysiological processes which include various forms of neoplasia, atherosclerosis, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, and abnormal wound healing.2 Upon ligand binding, the intrinsic tyrosine kinase activity of the PDGF receptor is activated. This leads to tyrosine phosphorylation of numerous proteins, including the receptor itself. Receptor autophosphorylation is essential for all subsequent steps of signal transduction. Importantly, the signaling cascade that follows from the action of PDGF on smooth muscle cell (SMC) PDGF receptors is believed to result in a significant contribution to the process of SMC proliferation and chem~taxis.~ This process is a crucial component of the sequence of events leading to restenosis after percutaneous transluminal coronary angioplasty procedure^.^ An inhibitor of the PDGF receptor tyrosine kinase activity would block its action. Such an inhibitor could potentially be utilized in the treatment of proliferative disorders linked to PDGF receptors, including postangioplasty restenosis. A series of 2,3-diarylacrylonitrile compounds has been prepared in our laboratories as epidermal growth factor receptor tyrosine kinase (EGF-RTK) inhibitors.5 I With several exceptions, these compounds were generally poor PDGF-RTK inhibitors. Compound 1 (RG13022): however, displayed modest inhibitory activity in both the EGFRTK' and PDGF-RTK cell-free assays (IC50 = 0.5-3 and 0.7-4 pM, respectively). As part of an effort to identify lead structures as PDGF-RTK inhibitors, we decided to