ABSTRACT
The powerful olefin metathesis reaction was employed for the construction of late-phase clinical agents SB1317 and SB1518. In both cases RCM seems to proceed only in the presence of an acid and to predominantly furnish trans isomers. In case of SB1518 it proceeded in the presence of acid HCl, while for SB1317, it mainly proceeds in the presence of TFA (trifluroacetic acid).
Subject(s)
Antineoplastic Agents/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Antineoplastic Agents/pharmacology , Bridged-Ring Compounds/pharmacology , Clinical Trials as Topic , Cyclization , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Janus Kinase 2/chemistry , Janus Kinase 2/metabolism , Lymphoma/drug therapy , Lymphoma/enzymology , Molecular Structure , Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/enzymology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , StereoisomerismABSTRACT
From a medicinal chemistry perspective, bicyclo[1.1.1]pentan-1-amine (1) has served as a unique and important moiety. Synthetically, however, this compound has received little attention, and only one scalable route to this amine has been demonstrated. Reduction of an easily available and potentially versatile intermediate, 1-azido-3-iodobicyclo[1.1.1]pentane (2), can offer both a flexible and scalable alternative to this target. Herein, we describe our scrutiny of this reportedly elusive transformation and report our ensuing success with this endeavor.
Subject(s)
Amines/chemistry , Azides/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Hydrocarbons, Iodinated/chemistry , Pentanes/chemistry , Pentanes/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Molecular StructureABSTRACT
SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.
Subject(s)
Arthritis, Experimental/drug therapy , Arthritis, Experimental/immunology , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Janus Kinase 2/antagonists & inhibitors , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Disease Models, Animal , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Male , Mice , Mice, Inbred C57BL , Rats , Rats, Inbred LewABSTRACT
Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.
Subject(s)
Antirheumatic Agents/chemical synthesis , Arthritis, Rheumatoid/drug therapy , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Janus Kinase 2/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Cell Line , Cell Membrane Permeability , Collagen Type II , Dogs , Female , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Janus Kinase 2/physiology , Macaca mulatta , Male , Mice , Mice, Nude , Microsomes/metabolism , Models, Molecular , Rats , Signal Transduction/drug effects , Solubility , Stereoisomerism , Structure-Activity Relationship , TYK2 Kinase/antagonists & inhibitorsABSTRACT
A virtual screen of our in-house database using various fingerprint techniques returned several triazine hits which were found to be mTOR inhibitors with a slight selectivity over PI3Kα. Using structure-guided lead optimization the inhibitory activity towards mTOR and PI3Kα was increased to the low nanomolar range. Exploiting shape differences in the binding-site allowed for the design of mTOR selective inhibitors. Focus on ligand efficiency ensured the inhibitors retained a low molecular weight and desirable drug-like properties.
Subject(s)
Morpholines/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Triazines/pharmacology , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Morpholines/chemistry , Protein Kinase Inhibitors/chemistry , Stereoisomerism , Structure-Activity Relationship , Triazines/chemistryABSTRACT
Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclin-Dependent Kinases/antagonists & inhibitors , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Janus Kinase 3/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Computer Simulation , Dogs , Drug Screening Assays, Antitumor , Female , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Rats , Stereoisomerism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC(50) = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC(50) = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC(50) = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.
Subject(s)
Antineoplastic Agents/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Janus Kinase 2/antagonists & inhibitors , Lymphoma/drug therapy , Primary Myelofibrosis/drug therapy , Pyrimidines/chemical synthesis , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Binding Sites , Bridged-Ring Compounds/pharmacokinetics , Bridged-Ring Compounds/pharmacology , Cell Line, Tumor , Dogs , Drug Screening Assays, Antitumor , Humans , In Vitro Techniques , Mice , Mice, Nude , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Solubility , Transplantation, Heterologous , Transplantation, HomologousABSTRACT
A series of alkenyl indazoles were synthesized and evaluated in Aurora kinase enzyme assays. Several promising leads were optimized for selectivity towards Aurora B. Excellent binding affinity and good selectivity were achieved with optimized compounds in isolated Aurora subfamily assays.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Aurora Kinases , Drug Evaluation, Preclinical , Models, Molecular , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolismABSTRACT
The synthetic procedure presented for the preparation of the title compounds requires 1,4-addition of bulky cuprates to cyclohexenones and subsequent reaction with electrophiles. However, the enolates generated by BF(3).OEt(2)-assistance suffer from lack of nucleophilicity. To circumvent this problem, we developed an indirect method consisting of the following three steps: (1) iodination of the cyclohexenones at the alpha position; (2) BF(3).OEt(2)-assisted 1,4-addition of cuprates (Ar(2)Cu(CN)Li(2), Ar = aryl) followed by quenching the enolates with water; (3) reaction of the alpha-iodo-beta-aryl-cylohexanones thus formed with EtMgBr to generate magnesium enolates. The enolates thus generated in this way showed a high reactivity toward ClP(O)(OEt)(2) to furnish enol phosphates. The aforementioned procedure was also applied to a synthesis of optically active Delta(9)-tetrahydrocannabinol. In addition, a naphthalene analogue of the latter compound was also synthesized in a similar way.
ABSTRACT
[reaction: see text] Transition metal-catalyzed arylation and alkenylation of the alpha-bromoalkenyl phosphonates were investigated with organoboranes and -borates. Arylation was successful with the aryl boronic acids and a palladium catalyst, while alkenylation was found to proceed with alkenyl borates and a nickel catalyst. In addition, an intramolecular Diels-Alder reaction of the diene prepared by the alkenylation afforded the corresponding adduct.
