CEP-11981: Identification of an orally bioavailable TIE-2/VEGF-R2 inhibitor with broad kinase inhibitory activity

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Orally bioavailable, dual inhibitors of TIE-2/VEGF-R2 were identified by elaborating the C3/N13 SAR around a fused pyrrolodihydroindazolocarbazole scaffold. This effort was guided by a co-crystal structure of a C3-tetrahydropyran (THP) analog complexed with TIE-2; this analog was anchored into the ATP binding pocket via a bidentate H-bonding motif of the pyrrolidinone with Ala905 and Glu903. Another apparent critical interaction involved Asp982 with the C3-THP oxygen. A variety of C3-ether, acyl, oxime, urea and aminopyrimidine analogs were prepared to further exploit this binding interaction; analogs were evaluated in enzymatic and cellular biochemical assays (inhibition of kinase phosphorylation) with preferred analogs having TIE-2/VEGF-R2 IC₅₀ values < 50 nM. In addition to their in vitro profiles, PK (rat) profiles were used to select compounds for further biological evaluation. In general, representatives from each structural class (except C3-urea analogs) possessed oral PK properties that predicted plasma exposures in excess of their respective cellular VEGF-R2 IC₅₀ values could readily be achieved. A lead compound, CEP-11981 (TIE-2 IC₅₀ = 22 ± 6 nM, VEGF-R2 IC₅₀ = 4 ± 1 nM, VEGF-R2 cell IC₅₀ < 10 nM and a kinase selectivity index S(90) against 217 kinases = 0.25 at 1 µM) was distinguished by demonstrating dose dependent increases in plasma exposure at 10, 30 and 55 mpk, and a dose related increase at 100 mpk, when administered as a suspension in Oraplus. CEP-11981 represents a potent, highly permeable, achiral multiplex inhibitor of TIE-2/VEGF-R2 with an ADME/PK profile across mice, rats, and monkeys that facilitates its in vivo evaluation in multiple murine tumor and angiogenesis models.