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•Chiral DHP as hinge binder provided high AKT1 selectivity over ROCK2/AGC kinases.•Emphasis on physicochemical properties over potency led to developable compounds.•Reducing the HB ...acceptor strength of compounds with high P-gp efflux improved Ppass.
During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model.
The p38 MAP kinase activity of two series of trisubstituted imidazoles (X
=
C, N) is reported, leading to compounds with highly potent cellular and in vivo activity.
Herein we report investigations ...into the p38α MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.
We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38α inhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme ...binding and inhibition of TNFα release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.
A general, simple and straightforward strategy for the synthesis of a novel series of 4,4-disubstituted 2,3,4,7-tetrahydroazepines is described. This route involves a one-pot Wittig ...olefination/N-allylation process on a five-membered hemi-aminal followed by a final ring closing metathesis reaction.
A general, simple and straightforward strategy for the synthesis of a novel series of 4,4-disubstituted 2,3,4,7-tetrahydroazepines is described. This route involves a one-pot Wittig olefination/N-allylation process on a five-membered hemi-aminal followed by a final ring closing metathesis reaction.
Herein we report investigations into the p38alpha MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a ...novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.
