A phase I trial evaluating the effects of plerixafor, G-CSF, and azacitidine for the treatment of myelodysplastic syndromes.

Interactions between the bone marrow microenvironment and MDS tumor clones play a role in pathogenesis and response to treatment. We hypothesized G-CSF and plerixafor may enhance sensitivity to azacitidine in MDS. Twenty-eight patients with MDS were treated with plerixafor, G-CSF and azacitidine with a standard 3 + 3 design.

Phase II Study of Propylene Glycol-Free Melphalan Combined with Carmustine, Etoposide, and Cytarabine for Myeloablative Conditioning in Lymphoma Patients Undergoing Autologous Stem Cell Transplantation.

The lyophilized formulation of melphalan has several limitations based on its marginal solubility, limited stability after reconstitution, and the requirement to reconstitute it in propylene glycol (PG). PG-free melphalan (Evomela; Spectrum Pharmaceuticals, Irvine CA) overcomes these limitations by using the solubilizing agent Captisol (Ligand Pharmaceuticals, Inc., LaJolla CA) to improve the stability of the reconstituted melphalan and avoid the potential toxicities of PG.

Phase I study of azacitidine following donor lymphocyte infusion for relapsed acute myeloid leukemia post allogeneic stem cell transplantation.

Donor lymphocyte infusion (DLI) without prophylactic immunosuppression has been used for relapsed AML after allogeneic stem cell transplant (allo-SCT). However DLI is associated with an increased incidence of acute Graft vs. Host Disease (aGVHD).

A study of high-dose lenalidomide induction and low-dose lenalidomide maintenance therapy for patients with hypomethylating agent refractory myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by bone marrow failure which frequently progress to acute myeloid leukemia. Patients who fail to respond to, or progress on first-line DNA hypomethylating agents (HMA) have a poor prognosis. Conventionally dosed lenalidomide has activity in 5q-MDS.

Discovery of N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis.

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.

Targeting bone marrow lymphoid niches in acute lymphoblastic leukemia.

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.

Structure-based parallel medicinal chemistry approach to improve metabolic stability of benzopyran COX-2 inhibitors.

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.

MMP-13 selective isonipecotamide alpha-sulfone hydroxamates.

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.

Orally bioavailable dual MMP-1/MMP-14 sparing, MMP-13 selective alpha-sulfone hydroxamates.

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.

Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.

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.

Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (Part 2).

In the preceding paper several compounds were reported as potent apical sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form.

Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (Part 1).

Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause of mortality in Western society. We believe that by preventing the reabsorption of bile acids, a minimally absorbed apical sodium-codependent bile acid transporter (ASBT) inhibitor would lower the serum cholesterol without the potential systemic side effects of an absorbed drug. A series of novel benzothiepines (3R,3R'-2,3,4,5-tetrahydro-5-aryl-1-benzothiepin-4-ol 1,1-dioxides) were synthesized and tested for their ability to inhibit the apical sodium dependent bile acid transport (ASBT)-mediated uptake of [(14)C]taurocholate (TC) in H14 cells.

A novel class of apical sodium co-dependent bile acid transporter inhibitors: the 1,2-benzothiazepines.

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.