ABSTRACT
Bruton's tyrosine kinase (BTK) is an essential node on the BCR signaling in B cells, which are clinically validated to play a critical role in B-cell lymphomas and various auto-immune diseases such as Multiple Sclerosis (MS), Pemphigus, and rheumatoid arthritis (RA). Although non-selective irreversible BTK inhibitors have been approved for oncology, due to the emergence of drug resistance in B-cell lymphoma associated with covalent inhibitor, there an unmet medical need to identify reversible, selective, potent BTK inhibitor as viable therapeutics for patients. Herein, we describe the identification of Hits and subsequence optimization to improve the physicochemical properties, potency and kinome selectivity leading to the discovery of a novel class of BTK inhibitors. Utilizing Met ID and structure base design inhibitors were synthesized with increased in vivo metabolic stability and oral exposure in rodents suitable for advancing to lead optimization.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Drug Discovery , Protein Kinase Inhibitors/pharmacokinetics , Agammaglobulinaemia Tyrosine Kinase/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Structure-Activity RelationshipABSTRACT
Since the approval of ibrutinib for the treatment of B-cell malignancies in 2012, numerous clinical trials have been reported using covalent inhibitors to target Bruton's tyrosine kinase (BTK) for oncology indications. However, a formidable challenge for the pharmaceutical industry has been the identification of reversible, selective, potent molecules for inhibition of BTK. Herein, we report application of Tethering-fragment-based screens to identify low molecular weight fragments which were further optimized to improve on-target potency and ADME properties leading to the discovery of reversible, selective, potent BTK inhibitors suitable for pre-clinical proof-of-concept studies.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Humans , Protein Kinase Inhibitors/pharmacologyABSTRACT
The identification of a selective CDK2, 7, 9 inhibitor 4 with improved permeability is described. Compound 4 exhibits comparable CDK selectivity profile to SNS-032, but shows improved permeability and higher bioavailability in mice.
Subject(s)
Oxazoles/chemistry , Oxazoles/pharmacokinetics , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Animals , Biological Availability , Mice , PermeabilityABSTRACT
Modifications of the isonipecotic acid fragment of SNS-032 results in analogs which are more permeable and lower effluxed than SNS-032. The enantiomerically pure synthesis and the in vivo profile of analog 20 is described.
Subject(s)
Cyclin-Dependent Kinase 2/antagonists & inhibitors , Isonipecotic Acids/chemistry , Oxazoles/chemical synthesis , Thiazoles/chemical synthesis , Animals , Combinatorial Chemistry Techniques , Isonipecotic Acids/pharmacology , Mice , Molecular Structure , Oxazoles/chemistry , Oxazoles/pharmacology , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
A series of 2-amino-pyrazolopyridines was designed and synthesized as Polo-like kinase (Plk) inhibitors based on a low micromolar hit. The SAR was developed to provide compounds exhibiting low nanomolar inhibitory activity of Plk1; the phenotype of treated cells is consistent with Plk1 inhibition. A co-crystal structure of one of these compounds with zPlk1 confirms an ATP-competitive binding mode.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Adenosine Triphosphate/chemistry , Amino Acid Motifs , Cell Cycle , Crystallography, X-Ray , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Phenotype , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Structure-Activity Relationship , Polo-Like Kinase 1ABSTRACT
Horner-Emmons fluoroolefination of an aryl aldehyde followed by introduction of a second fluorine via "FBr" addition provides an original approach to the preparation of 1-alkyl-2-aryl-1,2-difluoroethenes. The utility of this procedure is demonstrated by the preparation of (E and Z)-alpha,beta-difluorourocanic acid.
ABSTRACT
A bromotyrosine alkaloid family of antimicrobial agents was synthesized using the known structure of a natural inhibitor of the mycobacterial mycothiol S-conjugate amidase (MCA) as a template. This series of compounds represents a novel class of anti-infective agents against Gram-positive pathogens, including mycobacteria and meticillin- and vancomycin-resistant Staphylococcus aureus. The fact that these compounds are active against mycobacterial strains in which the MCA gene is deleted and against Gram-positive bacteria lacking mycothiol suggests the existence of an alternative target for these compounds. One member of this family, EXEG1706, was identified as the lead compound possessing low MICs (2.5-25 microg ml(-1)) for several clinical isolates, whilst having low toxicity for THP-1 monocytes and macrophages.
Subject(s)
Alkaloids/pharmacology , Anti-Bacterial Agents/pharmacology , Tyrosine/analogs & derivatives , Alkaloids/chemistry , Anti-Bacterial Agents/chemistry , Bacteria/drug effects , Cell Line , Fluoroacetates , Humans , Macrophages/drug effects , Models, Chemical , Molecular Structure , Monocytes/drug effects , Tyrosine/chemistry , Tyrosine/pharmacologyABSTRACT
An efficient total synthesis of (+/-)-alantrypinone 4 by hetero Diels-Alder reaction of a novel pyrazine diene 9 with either a functionalized 3-alkylideneoxindole or 3-methyleneoxindole itself is described. The Diels-Alder reactions provide both the desired regiochemistry and exo selectivity. An interesting anionic equilibration between alantrypinone 4 and its epimer 31 or between its ester analogues 23 and 24 has been demonstrated, and a mechanism has been proposed.
Subject(s)
Alkaloids/chemical synthesis , Indoles/chemical synthesis , Quinazolines/chemical synthesis , Alkaloids/chemistry , Indoles/chemistry , Magnetic Resonance Spectroscopy , Quinazolines/chemistry , Spectrometry, Mass, Fast Atom Bombardment , StereoisomerismABSTRACT
[reaction: see text] An efficient total synthesis of (+/-)-alantrypinone (1) and its 17-epi isomer (17) has been accomplished employing a novel aza-Diels-Alder reaction as the key step. The reaction sequence comprises 8 steps starting from anthranilic acid and proceeds in 13.5% overall yield. An interesting anionic equilibration between 1 and its epimer 17 has also been discovered.
ABSTRACT
The title compounds were prepared from a common precursor, a bis-THP-protected dihydroxyphenylacetic acid methyl ester. Key steps are the introduction of the alpha-hydroxyl group by Davis oxaziridine reagent and formation of the aldehydes by DIBALH ester reduction.
Subject(s)
3,4-Dihydroxyphenylacetic Acid/analogs & derivatives , 3,4-Dihydroxyphenylacetic Acid/chemical synthesis , Aldehydes/chemical synthesis , 3,4-Dihydroxyphenylacetic Acid/chemistry , Aldehydes/chemistry , Catechols , Hydrolysis , Hydroxyl Radical/chemistry , Indicators and ReagentsABSTRACT
Tryptamines disubstituted at the beta-position with fluorine have been synthesized as part of our research program to study the effects of fluorine substitution on the biological activities of neuroactive amines. Treatment of N-Boc-3-azidoacetyl indoles, prepared from readily available 2-chloracetylindoles, with dimethoxyethylamino sulfurtrifluoride produced the corresponding 3-(2-azido-1,1-difluoroethyl)indoles. Reduction of the azide to amine with hydrogen over Pd-C and careful removal of the N-Boc protecting group produced beta,beta-difluorotryptamines.
