In our continuing effort to expand the SAR of the quinoline domain of dihydropyrrolopyrazole series, we have discovered compound 15d, which demonstrated the antitumor efficacy with oral bioavailability. This effort also demonstrated that the PK/PD in vivo target inhibition paradigm is an effective approach to assess potential for antitumor efficacy. The dihydropyrrolopyrazole inhibitor 15d (LY2109761) is representative of a novel series of antitumor agents.
Electrophilic alkylations of remote double bonds by allylic moieties are important carbon-carbon bond forming reactions in terpene metabolism and related biomimetic olefin cyclizations.1"4The enzymatic and nonenzymatic reactions are both characterized by a high degree of stereoselectivity. Two explanations have evolved for this phenomenon.5 One is the reactions are concerted. This is attractive since stereospecificity is a logical result of the synchronous changes in bonding that occur in concerted reactions. The other explanation is a nonconcerted process involving a series of conformationally rigid intermediates where topology is maintained between the initiation and termination steps.
Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-beta type I receptor (TGF-beta RI), TGF-beta RII, and mixed lineage kinase-7 (MLK-7). These compounds were found to be potent TGF-beta RI inhibitors and selective versus TGF-beta RII and MLK-7 kinases. Benzimidazole derivative 8b was active in an in vivo target (TGF-beta RI) inhibition assay.
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