ABSTRACT
Chemical optimization of the 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (THPP) scaffold was conducted with a focus on cellular potency while maintaining high selectivity against PI3K isoforms. Compound 11f was identified as a potent, highly selective and orally available PI3Kδ inhibitor. In addition, 11f exhibited efficacy in an in vivo antibody production model. The desirable drug-like properties and in vivo efficacy of 11f suggest its potential as a drug candidate for the treatment of autoimmune diseases and leukocyte malignancies.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors/chemistry , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Animals , Cells, Cultured , Class I Phosphatidylinositol 3-Kinases/metabolism , Female , Humans , Mice, Inbred BALB C , Molecular Docking Simulation , Phosphoinositide-3 Kinase Inhibitors/pharmacokinetics , Pyrrolidines/pharmacokineticsABSTRACT
Chemical optimization of pyrazolopyridine 1, focused on cellular potency, isoform selectivity and microsomal stability, led to the discovery of the potent, selective and orally available PI3Kδ inhibitor 5d. On the basis of its desirable potency, selectivity and pharmacokinetic profiles, 5d was tested in the trinitrophenylated aminoethylcarboxymethyl-Ficoll (TNP-Ficoll)-induced antibody production model, and showed higher antibody inhibition than a 4-fold oral dose of the starting compound 1. These excellent results suggest that 5d is a potential candidate for further studies in the treatment of autoimmune diseases and leukocyte malignancies.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Animals , Cell Proliferation/drug effects , Class I Phosphatidylinositol 3-Kinases/metabolism , Computational Biology , Dose-Response Relationship, Drug , Female , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
Phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a potent PI3Kδ inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kδ inhibitor with reduced selectivity against other PI3Ks. To improve the trade-off between selectivity and PK profile, structure-activity relationship (SAR) studies of terminal substituents on the pyrolidine ring were conducted. As a result, we developed potent PI3Kδ inhibitors with good oral availability. In particular, the representative compound 15j showed excellent selectivity for PI3Kδ over other PI3Ks with good oral exposure in mice.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Administration, Oral , Animals , Class I Phosphatidylinositol 3-Kinases , Female , Humans , Mice, Inbred BALB C , Molecular Docking Simulation , Molecular Structure , Nuclear Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/administration & dosage , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Pyridines/administration & dosage , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Stereoisomerism , Structure-Activity Relationship , Transcription Factors/antagonists & inhibitorsABSTRACT
D-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze.
Subject(s)
D-Amino-Acid Oxidase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyridazines/pharmacology , Animals , D-Amino-Acid Oxidase/chemistry , Dizocilpine Maleate/pharmacology , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , HEK293 Cells , Humans , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory/drug effects , Mice , Models, Molecular , Permeability , Protein Conformation , Pyridazines/chemical synthesis , Pyridazines/chemistry , Pyridazines/metabolism , Structure-Activity RelationshipABSTRACT
The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K(i)* values of 0.38 +/- 0.29 and 1.5 +/- 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC(50) = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.
Subject(s)
Aza Compounds/chemical synthesis , Indoles/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Aurora Kinase A , Aurora Kinase B , Aurora Kinases , Aza Compounds/chemistry , Aza Compounds/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Histones/metabolism , Humans , Indoles/chemistry , Indoles/pharmacology , Mice , Neoplasm Transplantation , Phosphorylation , Stereoisomerism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Exploration of the SAR around a series of 3,5-disubstituted-1H-pyrrolo[2,3-b]pyridines led to the discovery of novel pyrrolopyridine inhibitors of the IGF-1R tyrosine kinase. Several compounds demonstrated nanomolar potency in enzyme and cellular mechanistic assays.
Subject(s)
Protein Kinase Inhibitors/chemistry , Pyridines/chemistry , Pyrroles/chemistry , Receptor, IGF Type 1/antagonists & inhibitors , Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Receptor, IGF Type 1/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis of a 7-azaindole series of novel, potent B-Raf kinase inhibitors using knowledge-based design was carried out. Compound 6h exhibits not only excellent potency in both the enzyme assay (IC(50)=2.5 nM) and the cellular assay (IC(50)=63 nM), but also has an outstanding selectivity profile against other kinases.
Subject(s)
Chemistry, Pharmaceutical/methods , Indoles/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/metabolism , Drug Design , Humans , Inhibitory Concentration 50 , Models, Biological , Models, Chemical , Molecular Structure , Phosphotransferases/metabolism , Protein Kinase Inhibitors/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Substrate SpecificityABSTRACT
The copper(II) triflate- and hafnium(IV) triflate-catalyzed aminomethylation of indole (2) with an N-silyl-N,O-acetal 1 containing a trichloromethyl group provides the primary amine derivative (3a) in modest yield. When 1 equiv of trimethylchlorosilane (TMSCl) was added to the reaction mixture, the reaction proceeded smoothly, and the yield of 3a was dramatically improved (>90%). The use of this catalytic system permitted the introduction of an aminomethyl group onto indoles 2a-h bearing a variety of functional groups, which appears to deactivate the Lewis acid, in 52-92% yields. Hf(OTf)4-doped TMSCl catalyzed the successful aminomethylation of various electron-rich aromatic compounds 4a-j to produce 1-aryl-trichloroethylamine derivatives 5a-j.
