ABSTRACT
Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.
Subject(s)
Antirheumatic Agents/chemistry , Carbazoles/chemistry , Protein-Tyrosine Kinases/antagonists & inhibitors , Quinazolinones/chemistry , Administration, Oral , Agammaglobulinaemia Tyrosine Kinase , Animals , Antirheumatic Agents/chemical synthesis , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/pathology , Biological Availability , Carbazoles/chemical synthesis , Carbazoles/pharmacokinetics , Carbazoles/pharmacology , Cell Line , Crystallography, X-Ray , Dogs , Humans , Macaca fascicularis , Mice , Microsomes, Liver/metabolism , Permeability , Protein-Tyrosine Kinases/chemistry , Quinazolinones/chemical synthesis , Quinazolinones/pharmacokinetics , Quinazolinones/pharmacology , Structure-Activity RelationshipABSTRACT
Tau-tubulin kinase 1 (TTBK1) is a dual-specificity (serine/threonine and tyrosine) kinase belonging to the casein kinase 1 superfamily. TTBK1 is a neuron-specific kinase that regulates tau phosphorylation. Hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer's disease. Two kinase-domain constructs of TTBK1 were expressed in a baculovirus-infected insect-cell system and purified. The purified TTBK1 kinase-domain proteins were crystallized using the hanging-drop vapor-diffusion method. X-ray diffraction data were collected and the structure of TTBK1 was determined by molecular replacement both as an apo structure and in complex with a kinase inhibitor.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/chemistry , Animals , Baculoviridae/genetics , Crystallization , Crystallography, X-Ray , Electrophoresis, Polyacrylamide Gel , Humans , Magnetic Resonance Spectroscopy , Protein Conformation , Sf9 Cells , Substrate SpecificityABSTRACT
A new class of lymphocyte function-associated antigen-1 (LFA-1) antagonists is described. Elaboration of the 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold resulted in the synthesis of potent inhibitors of the LFA-1/ICAM-1 interaction. Along with the in vitro activity, we present the X-ray crystal structure of the complex of compound 9b, in a novel binding mode to the I-domain of LFA-1.
Subject(s)
Chemistry, Pharmaceutical/methods , Lymphocyte Function-Associated Antigen-1/chemistry , Pyrroles/chemistry , Crystallography, X-Ray , Drug Design , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Stereoisomerism , Temperature , X-RaysABSTRACT
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta(2)-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells and antigen-presenting cells. Evidence from both animal models and clinical trials provides support for LFA-1 as a target in several different inflammatory diseases. This paper describes the de novo design, synthesis and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.
