ABSTRACT
Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.
Subject(s)
Drug Discovery , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Quinolines/pharmacology , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Dose-Response Relationship, Drug , Humans , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Quinolines/chemical synthesis , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yield of the initial synthesis. A second generation synthesis is described that features a Noyori dynamic kinetic resolution, a highly diastereoselective allylation, and a novel oxazoline-assisted piperidinone forming reaction to provide AM-8553 in 35.6% yield and 11 steps.
Subject(s)
Acetates/chemical synthesis , Antineoplastic Agents/chemical synthesis , Piperidones/chemical synthesis , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Tumor Suppressor Protein p53/antagonists & inhibitors , Acetates/chemistry , Amino Alcohols/chemical synthesis , Amino Alcohols/chemistry , Antineoplastic Agents/chemistry , Cyclization , Humans , Lactones/chemical synthesis , Lactones/chemistry , Models, Molecular , Oxazoles/chemical synthesis , Oxazoles/chemistry , Piperidones/chemistry , StereoisomerismABSTRACT
A bis-amide antagonist of Smoothened, a seven-transmembrane receptor in the Hedgehog signaling pathway, was discovered via high throughput screening. In vitro and in vivo experiments demonstrated that the bis-amide was susceptible to N-acyl transferase mediated amide scission. Several bioisosteric replacements of the labile amide that maintained in vitro potency were identified and shown to be metabolically stable in vitro and in vivo.
Subject(s)
Acyltransferases/antagonists & inhibitors , Amides/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Acyltransferases/metabolism , Amides/chemistry , Amides/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , High-Throughput Screening Assays , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model.
Subject(s)
Hedgehog Proteins/antagonists & inhibitors , Phthalazines/chemistry , Piperazines/chemistry , Pyridazines/chemistry , Receptors, Steroid/chemistry , Animals , Hedgehog Proteins/metabolism , Humans , Mice , Microsomes, Liver/metabolism , Phthalazines/chemical synthesis , Phthalazines/pharmacokinetics , Piperazines/chemical synthesis , Piperazines/pharmacokinetics , Pregnane X Receptor , Pyridazines/chemical synthesis , Pyridazines/pharmacokinetics , Rats , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/metabolism , Receptors, Steroid/metabolism , Signal Transduction , Smoothened Receptor , Structure-Activity Relationship , Tylosin/analogs & derivativesABSTRACT
The Hedgehog (Hh) signaling pathway regulates cell proliferation and differentiation in developing tissues, and abnormal activation of the Hh pathway has been linked to several tumor subsets. As a transducer of Hh signaling, the GPCR-like protein Smoothened (Smo) is a promising target for disruption of unregulated Hh signaling. A series of 1-amino-4-arylphthalazines was developed as potent and orally bioavailable inhibitors of Smo. A representative compound from this class demonstrated significant tumor volume reduction in a mouse medulloblastoma model.
Subject(s)
Phthalazines/chemistry , Phthalazines/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cell Line, Tumor , Cytochrome P-450 Enzyme System/drug effects , Drug Design , Hedgehog Proteins , Humans , Medulloblastoma/drug therapy , Medulloblastoma/pathology , Mice , Phthalazines/chemical synthesis , Signal Transduction , Smoothened ReceptorABSTRACT
[reaction: see text] An efficient synthesis of the C20-C32 segment of the phorboxazoles has been achieved using an enantioselective hetero Diels-Alder reaction catalyzed by Jacobsen's Cr(III) amino indanol Schiff base catalyst.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Oxazoles/chemical synthesis , Catalysis , Chromium/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Indicators and Reagents , Molecular Structure , Oxazoles/chemistry , Schiff Bases/chemistryABSTRACT
The C1-C17 bis-oxane subunit 22 of phorboxazole B is efficiently synthesized by exploiting differential reactivities between similar substituents on the hydropyran rings in 4. Selective dihydroxylation of the equatorial vinyl group, hydroboration of the axial vinyl group, and intramolecular Mitsunobu lactonization serve to fully differentiate the similar hydropyrans.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Oxazoles/chemistry , Oxazoles/chemical synthesis , Pyrans/chemical synthesis , Catalysis , Indicators and Reagents , Molecular Structure , Pyrans/chemistryABSTRACT
[reaction: see text] meso-Tetraol bis(allylic acetates) 2 and 5 were synthesized via two-directional chain elongation. A palladium-mediated, ligand-controlled desymmetrization provided the desired bis-oxanes in greater than 98% ee. Bis-oxanes 1 and 4 represent potential synthetic intermediates for the C3-C17 subunits of phorboxazoles A and B.
