TrkA kinase inhibitors from a library of modified and isosteric Staurosporine aglycone.
An immobilized Staurosporine aglycone isostere where one of the indole nitrogen atoms was replaced by carbon has been sequentially functionalized to generate compounds inhibiting TrkA kinase. In the first phase, initial screening of a library of C13-hydroxymethyl-7-oxo-indenopyrrolocarbazoles resulted in several potent compounds, one of which was further optimized to generate the corresponding carbamates on solid phase. Some of the major carbamate diastereomers were found to be several-fold more potent than their alcohol parents. Synthesis, SAR analysis, kinase selectivity, and anti-tumor properties of a TrkA inhibitor (12a) are discussed.
Cephalon, Inc., Discovery Research, 145 Brandywine Parkway, West Chester, PA 19380, USA. rtripath@cephalon.com
Rabindranath
R
Tripathy
Thelma S
TS
Angeles
Shi X
SX
Yang
John P
JP
Mallamo
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008968:Molecular Conformation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries; D019311:Staurosporine / Q000031:analogs & derivatives / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002227:Carbazoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D054852:Small Molecule Libraries; D020917:Receptor, trkA; D019311:Staurosporine