ABSTRACT
Structural analysis of the known NIK inhibitor 3 bound to the kinase domain of TTBK1 led to the design and synthesis of a novel class of azaindazole TTBK1 inhibitors exemplified by 8 (cell IC50: 571 nM). Systematic optimization of this series of analogs led to the discovery of 31, a potent (cell IC50: 315 nM) and selective TTBK inhibitor with suitable CNS penetration (rat Kp,uu: 0.32) for in vivo proof of pharmacology studies. The ability of 31 to inhibit tau phosphorylation at the disease-relevant Ser 422 epitope was demonstrated in both a mouse hypothermia and a rat developmental model and provided evidence that modulation of this target may be relevant in the treatment of Alzheimer's disease and other tauopathies.
Subject(s)
Brain/metabolism , Drug Design , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , tau Proteins/metabolism , Animals , Humans , Indazoles/chemistry , Indazoles/metabolism , Indazoles/pharmacology , Mice , Molecular Targeted Therapy , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemistry , RatsABSTRACT
Structural analysis of a known apoptosis signal-regulating kinase 1 (ASK1) inhibitor bound to its kinase domain led to the design and synthesis of the novel macrocyclic inhibitor 8 (cell IC50 = 1.2 µM). The profile of this compound was optimized for CNS penetration following two independent strategies: a rational design approach leading to 19 and a parallel synthesis approach leading to 26. Both analogs are potent ASK1 inhibitors in biochemical and cellular assays (19, cell IC50 = 95 nM; 26, cell IC50 = 123 nM) and have moderate to low efflux ratio (ER) in an MDR1-MDCK assay (19, ER = 5.2; 26, ER = 1.5). In vivo PK studies revealed that inhibitor 19 had moderate CNS penetration (Kpuu = 0.17) and analog 26 had high CNS penetration (Kpuu = 1.0).
Subject(s)
MAP Kinase Kinase Kinase 5/antagonists & inhibitors , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Animals , Brain/metabolism , Drug Design , Humans , MAP Kinase Kinase Kinase 5/metabolism , Macrocyclic Compounds/chemistry , Molecular Structure , RatsABSTRACT
Cyclization of an aryl radical at the ipso position of a p-O-aryl-substituted acetamide or benzamide generates oxindoles or quinolones bearing spirocyclohexadienone rings. This versatile reaction is applied to formal syntheses of the vasopressin inhibitor SR121463A and aza-galanthamine.
