ABSTRACT
Aromatic ring isosteres and rigidified saturated hydrocarbons are important motifs to enable drug discovery. Herein we disclose [2]-ladderanes as a class of meta-substituted aromatic ring isosteres and rigidified cyclohexanes. A straightforward synthesis of the building blocks is presented along with representative derivatization. Preliminary studies reveal that the [2]-ladderanes offer similar metabolic and physicochemical properties thus establishing this class of molecules as interesting motifs.
Subject(s)
CyclohexanesABSTRACT
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Apoptosis/physiology , Neovascularization, Physiologic/physiology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Animals , Cell Survival , Humans , Mice , Mice, Nude , Phosphorylation , Xenograft Model Antitumor AssaysABSTRACT
Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Herein we report the discovery of potent and selective triazolopyridazine small molecules that inhibit c-Met activity.
Subject(s)
Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridazines/chemical synthesis , Triazoles/chemical synthesis , Animals , Crystallography, X-Ray , Hepatocyte Growth Factor/physiology , In Vitro Techniques , Mice , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Phosphorylation , Proto-Oncogene Proteins c-met/chemistry , Proto-Oncogene Proteins c-met/metabolism , Pyridazines/chemistry , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Rats , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Critical to these processes is signaling through VEGFR-2 or the kinase insert domain receptor (KDR) upon stimulation by its ligand VEGF. Herein, we report the discovery of 2,3-dihydro-1,4-benzoxazines as inhibitors of intrinsic KDR activity (IC 50 < 0.1 microM) and human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 < 0.1 microM. More specifically, compound 16 was identified as a potent (KDR: < 1 nM and HUVEC: 4 nM) and selective inhibitor that exhibited efficacy in angiogenic in vivo models. In addition, this series of molecules is typically well-absorbed orally, further demonstrating the 2,3-dihydro-1,4-benzoxazine moiety as a promising platform for generating kinase-based antiangiogenic therapeutic agents.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Benzoxazines/administration & dosage , Neoplasms/blood supply , Neovascularization, Pathologic/prevention & control , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/chemistry , Animals , Benzoxazines/chemical synthesis , Benzoxazines/chemistry , Biological Availability , Cell Line , Cell Proliferation/drug effects , Corneal Neovascularization/blood , Crystallography, X-Ray , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , Female , Humans , Injections, Subcutaneous , Ligands , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Models, Animal , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
The hydrolytic kinetic resolution (HKR) of terminal epoxides catalyzed by chiral (salen)Co(III) complex 1 x OAc affords both recovered unreacted epoxide and 1,2-diol product in highly enantioenriched form. As such, the HKR provides general access to useful, highly enantioenriched chiral building blocks that are otherwise difficult to access, from inexpensive racemic materials. The reaction has several appealing features from a practical standpoint, including the use of H(2)O as a reactant and low loadings (0.2-2.0 mol %) of a recyclable, commercially available catalyst. In addition, the HKR displays extraordinary scope, as a wide assortment of sterically and electronically varied epoxides can be resolved to > or = 99% ee. The corresponding 1,2-diols were produced in good-to-high enantiomeric excess using 0.45 equiv of H(2)O. Useful and general protocols are provided for the isolation of highly enantioenriched epoxides and diols, as well as for catalyst recovery and recycling. Selectivity factors (k(rel)) were determined for the HKR reactions by measuring the product ee at ca. 20% conversion. In nearly all cases, k(rel) values for the HKR exceed 50, and in several cases are well in excess of 200.
