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Discovery of novel Bruton's tyrosine kinase (BTK) inhibitors bearing a pyrrolo[2,3-d]pyrimidine scaffold. 2015

Xinge Zhao, and Wei Huang, and Yazhou Wang, and Minhang Xin, and Qiu Jin, and Jianfeng Cai, and Feng Tang, and Yong Zhao, and Hua Xiang
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.

A series of novel reversible BTK inhibitors was designed based on the structure of the recently reported preclinical drug RN486. Knowledge of the binding mode of RN486 led to the design of new inhibitors that utilized pyrrolo[2,3-d]pyrimidine to conformationally restrain key pharmacophoric groups within the molecule. Comprehensive SAR was disclosed and the most promising compound 4x displayed superior activity both in BTK enzyme (IC50=4.8nM) and cellular inhibition (IC50=17nM) assays to that of RN486.

UI MeSH Term Description Entries
D011505 Protein-Tyrosine Kinases Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors. Tyrosine Protein Kinase,Tyrosine-Specific Protein Kinase,Protein-Tyrosine Kinase,Tyrosine Kinase,Tyrosine Protein Kinases,Tyrosine-Specific Protein Kinases,Tyrosylprotein Kinase,Kinase, Protein-Tyrosine,Kinase, Tyrosine,Kinase, Tyrosine Protein,Kinase, Tyrosine-Specific Protein,Kinase, Tyrosylprotein,Kinases, Protein-Tyrosine,Kinases, Tyrosine Protein,Kinases, Tyrosine-Specific Protein,Protein Kinase, Tyrosine-Specific,Protein Kinases, Tyrosine,Protein Kinases, Tyrosine-Specific,Protein Tyrosine Kinase,Protein Tyrosine Kinases,Tyrosine Specific Protein Kinase,Tyrosine Specific Protein Kinases
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D011758 Pyrroles Azoles of one NITROGEN and two double bonds that have aromatic chemical properties. Pyrrole
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077329 Agammaglobulinaemia Tyrosine Kinase A non-receptor tyrosine kinase that is essential for the development, maturation, and signaling of B-LYMPHOCYTES. It contains an N-terminal zinc finger motif and localizes primarily to the PLASMA MEMBRANE and nucleus of B-lymphocytes. Mutations in the gene that encode this kinase are associated with X-LINKED AGAMMAGLOBULINEMIA. B Cell Progenitor Kinase,Bruton's Tyrosine Kinase,Bruton Tyrosine Kinase,Brutons Tyrosine Kinase,Kinase, Agammaglobulinaemia Tyrosine,Kinase, Bruton's Tyrosine,Tyrosine Kinase, Agammaglobulinaemia,Tyrosine Kinase, Bruton's
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking

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