ABSTRACT
Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.
Subject(s)
Matrix Metalloproteinase 13/drug effects , Matrix Metalloproteinase Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors/pharmacology , Osteoarthritis/drug therapy , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Tetrazoles/chemical synthesis , Tetrazoles/pharmacology , Animals , Cartilage, Articular/drug effects , Cartilage, Articular/pathology , Collagenases/drug effects , Dogs , Drug Design , Humans , Kidney/metabolism , Macaca fascicularis , Male , Matrix Metalloproteinase Inhibitors/toxicity , Models, Molecular , Organic Anion Transporters, Sodium-Independent/metabolism , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
In acute lymphoblastic leukemia (ALL) the bone marrow microenvironment provides growth and survival signals that may confer resistance to chemotherapy. Granulocyte colony-stimulating factor (G-CSF) potently inhibits lymphopoiesis by targeting stromal cells that comprise the lymphoid niche in the bone marrow. To determine whether lymphoid niche disruption by G-CSF sensitizes ALL cells to chemotherapy, we conducted a pilot study of G-CSF in combination with chemotherapy in patients with relapsed or refractory ALL. Thirteen patients were treated on study; three patients achieved a complete remission (CR/CRi) for an overall response rate of 23%. In the healthy volunteers, G-CSF treatment disrupted the lymphoid niche, as evidenced by reduced expression of CXCL12, interleukin-7, and osteocalcin. However, in most patients with relapsed/refractory ALL expression of these genes was markedly suppressed at baseline. Thus, although G-CSF treatment was associated with ALL cell mobilization into the blood, and increased apoptosis of bone marrow resident ALL cells, alterations in the bone marrow microenvironment were modest and highly variable. These data suggest that disruption of lymphoid niches by G-CSF to sensitize ALL cells to chemotherapy may be best accomplished in the consolidation where the bone marrow microenvironment is more likely to be normal.
Subject(s)
Bone Marrow/pathology , Neoplastic Stem Cells/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Stem Cell Niche , Tumor Microenvironment , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B-Cell Activating Factor/biosynthesis , B-Cell Activating Factor/genetics , Chemokine CXCL12/biosynthesis , Chemokine CXCL12/genetics , Drug Resistance, Neoplasm/physiology , Etoposide/administration & dosage , Female , Filgrastim/administration & dosage , Filgrastim/pharmacology , Gene Expression Regulation, Leukemic/drug effects , Humans , Ifosfamide/administration & dosage , Interleukin-7/biosynthesis , Interleukin-7/genetics , Male , Mesna/administration & dosage , Middle Aged , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplastic Stem Cells/drug effects , Osteocalcin/biosynthesis , Osteocalcin/genetics , Pilot Projects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Recurrence , Remission Induction , Salvage Therapy , Stem Cell Niche/drug effects , Tumor Microenvironment/drug effects , Young AdultABSTRACT
Combination of the structure-based design and solid-phase parallel synthesis provided an integrated approach to rapidly develop the structure-activity relationship of benzopyran COX-2 inhibitors. Binding free energies predicted by free energy perturbation theory yielded good agreement with experimental results. New potent and selective lead compounds with improved metabolic properties were identified.
Subject(s)
Benzopyrans/chemistry , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2/chemistry , Microsomes/metabolism , Animals , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Chemistry, Pharmaceutical , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Humans , Protein Binding , Rats , Structure-Activity Relationship , ThermodynamicsABSTRACT
A series of phenyl piperidine alpha-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13, are dual-sparing of MMP-1 and MMP-14 (MT1-MMP) and exhibit oral bioavailability in rats.
Subject(s)
Matrix Metalloproteinase Inhibitors , Administration, Oral , Animals , Biological Availability , Hydroxamic Acids/administration & dosage , Matrix Metalloproteinase 1/drug effects , Matrix Metalloproteinase 14/drug effects , Piperidines , Rats , Small Molecule Libraries , Solubility , Substrate Specificity , SulfonesABSTRACT
A series of N-aryl isonipecotamide alpha-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13.
Subject(s)
Hydroxamic Acids/chemistry , Matrix Metalloproteinase Inhibitors , Administration, Oral , Amides , Animals , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Inhibitory Concentration 50 , Rats , Small Molecule Libraries , Solubility , Substrate Specificity , SulfonesABSTRACT
Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.
Subject(s)
Matrix Metalloproteinase Inhibitors , Osteoarthritis/drug therapy , Picolinic Acids/chemistry , Protease Inhibitors/chemistry , Tetrazoles/chemistry , Administration, Oral , Animals , Binding Sites , Cartilage/drug effects , Cartilage/metabolism , Catalytic Domain , Crystallography, X-Ray , Disease Models, Animal , Drug Discovery , Matrix Metalloproteinase 13/metabolism , Picolinic Acids/chemical synthesis , Picolinic Acids/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Rats , Tetrazoles/chemical synthesis , Tetrazoles/pharmacology , Zinc/chemistryABSTRACT
A series of 5-aryl-3,3-dibutyl-7-(dimethylamino)-1,2-benzothiazepin-4-ol 1,1-dioxides were prepared and were found to inhibit the apical sodium co-dependent bile acid transporter (ASBT) for the potential treatment for hyperlipidemia. Several 1,2-benzothiazepines exhibited low nanomolar in vitro activity. The synthesis and initial in vitro potency data is presented for this novel class of compounds.
