ABSTRACT
A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Tryptophan/chemistry , Animals , Binding Sites , Computer Simulation , Female , Injections, Intravenous , Liver/metabolism , Male , Mice , Mice, Inbred BALB C , Mutation , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Structure, Tertiary , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(α, ß, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, ß, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Cytochrome P-450 CYP3A Inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Arthritis, Rheumatoid/enzymology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Benzimidazoles/therapeutic use , Cell Line , Cytochrome P-450 CYP3A , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Humans , Inhibitory Concentration 50 , Models, Molecular , Phosphatidylinositol 3-Kinases/chemistry , Protein Conformation , Substrate Specificity , Time FactorsABSTRACT
Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Indazoles/pharmacology , Neoplasms/drug therapy , Phosphoinositide-3 Kinase Inhibitors , Sulfonamides/pharmacology , Administration, Oral , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Biological Availability , Cell Line, Tumor , Drug Screening Assays, Antitumor , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Humans , Indazoles/administration & dosage , Indazoles/pharmacokinetics , Indazoles/therapeutic use , Magnetic Resonance Spectroscopy , Molecular Structure , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic useABSTRACT
A series of 4'-substituted ribonucleoside derivatives has been prepared and evaluated for inhibition of hepatitis C virus (HCV) RNA replication in cell culture. The most potent and non-cytotoxic derivative was compound 28 (4'-azidocytidine, R1479) with an IC(50) of 1.28 microM in the HCV replicon system. The triphosphate of compound 28 was prepared and shown to be an inhibitor of RNA synthesis mediated by NS5B (IC(50)=320 nM), the RNA polymerase encoded by HCV. Data on related analogues have been used to generate some preliminary requirements for activity within this series of nucleosides.
Subject(s)
Antiviral Agents/chemistry , Chemistry, Pharmaceutical/methods , Cytidine/analogs & derivatives , Hepacivirus/genetics , Ribonucleosides/chemistry , Virus Replication/drug effects , Cytidine/pharmacology , Drug Design , Drug Evaluation, Preclinical , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Nucleosides/chemistry , RNA/chemistry , UridineABSTRACT
In our continued effort to identify selective MRP1 modulators, we have developed two novel templates, 3 and 4, through rational drug design by identifying the key pharmacophore interaction at the 7-position of the pyrrolopyrimidine template 1. Further synthesis and SAR work on these novel templates gave a number of potent MRP1 modulators with great selectivity against Pgp. Additional studies to reduce the CYP3A4 inhibition are also reported. Several compounds of these classes were subjected to in vivo xenograft studies and in vivo efficacies were demonstrated.
