alpha-Piperidine-beta-sulfone hydroxamate derivatives were explored that are potent for matrix metalloproteinases (MMP)-2, -9, and -13 and are sparing of MMP-1. The investigation of the beta-sulfones subsequently led to the discovery of hitherto unknown alpha-sulfone hydroxamates that are superior to the corresponding beta-sulfones in potency for target MMPs, selectivity vs MMP-1, and exposure when dosed orally. alpha-Piperidine-alpha-sulfone hydroxamate 35f (SC-276) was advanced through antitumor and antiangiogenesis assays and was selected for development. Compound 35f demonstrates excellent antitumor activity vs MX-1 breast tumor in mice when dosed orally as monotherapy or in combination with paclitaxel.
α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP's-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.
Matrix metalloproteinases (MMPs) are known to play a role in cell growth, invasion, angiogenesis, metastasis, and bone degradation, all important events in the pathogenesis of cancer. Multiple myeloma is a B-cell cancer characterized by the proliferation of malignant plasma cells in the bone marrow, increased angiogenesis, and the development of osteolytic bone disease. The role of MMPs in the development of multiple myeloma is poorly understood. Using SC-964, a potent inhibitor of several MMPs (MMP-2, -3, -8, -9, and -13), we investigated the role of MMPs in the 5T2MM murine model. Reverse transcriptase-polymerase chain reaction demonstrated the presence of mRNA for MMP-2, -8, -9, and -13 in 5T2MM-diseased bone marrow. Mice bearing 5T2MM cells were given access to food containing SC-964. The concentration of SC-964 measured in the plasma of mice after 11 days of treatment was able to inhibit MMP-9 activity in gelatin zymography. Treatment of 5T2MM-bearing mice resulted in a significant reduction in tumor burden, a significant decrease in angiogenesis, and partially protective effect against the development of osteolytic bone disease. The direct role of MMPs in these different processes was confirmed by in vitro experiments. All these results support the multifunctional role of MMPs in the development of multiple myeloma.
Hematopoietic prostaglandin D synthase (HPGDS) is primarly expressed in mast cells, antigen-presenting cells, and Th-2 cells. HPGDS converts PGH 2 into PGD 2 , a mediator thought to play a pivotal role in airway allergy and inflammatory processes. In this letter, we report the discovery of an orally potent and selective inhibitor of HPGDS that reduces the antigen-induced response in allergic sheep.KEYWORDS Hematopoietic prostaglandin D synthase (HPGDS), PGH 2 , PGD 2 , airway allergy, inflammatory processes, cyclooxygenase (COX) A sthma is a chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing in susceptible individuals. 1,2 Prostaglandin D 2 (PGD 2 ), a mediator of allergy and inflammation, is produced by mast cells and Th-2 cells in a variety of human tissues. PGD 2 is the most abundant de novo cyclooxygenase-derived mediator produced following IgE-mediated degranulation of mast cells. 3 The mast cell, following allergen-provoked degranulation, is believed to be the major source of PGD 2 found in the nasal exudates of patients with allergic rhinitis. PGD 2 levels increase dramatically in bronchoalveolar lavage fluid following allergen challenge, and the observation that patients with asthma exhibit bronchoconstriction upon inhalation of PGD 2 underscores the pathologic consequences of high levels of PGD 2 in the lung. 4 Treatment with PGD 2 produces significant nasal congestion and fluid secretion in man and dogs, and PGD 2 is 10 times more potent than histamine and 100 times more potent than bradykinin in producing nasal blockage in humans, demonstrating a role for PGD 2 in allergic rhinitis. 5,6 Mast cell-derived PGD 2 exerts its effect by activating two distinct G-protein-coupled receptors (GPCRs): the DP-1 receptor, a member of the prostanoid receptor subfamily, and the recently discovered chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTH 2 receptor). The DP-1 receptor is localized on the nasal vasculature and in mucin-secreting cells and is associated with tissue swelling and a concomitant increase in nasal airway resistance, while the CRTH 2 receptor is expressed on a subset of infiltrating T cells in inflamed nasal mucosa and is associated with the induction of chemotactic migration and/or activation of Th-2, eosinophils, and basophils. 7-9 Collectively, these data support a role for PGD 2 in inflammatory diseases of the upper airways and suggest that blockade of PGD 2 action at either or both receptors might be beneficial for the treatment of nasal allergies and other PGD 2 -mediated inflammatory conditions. This has created significant interest in both DP-1 and CRTH 2 as targets, and several publications have appeared describing inhibitor design. 10,11 PGD 2 is synthesized from arachidonic acid via the oxidation by cyclooxygenase PGH 2 (COX) and isomerization of PGH 2 to PGD 2 by prostaglandin D synthase (PGDS). Hematopoietic PGDS (HPGDS) is responsible for the synthesis of PGD 2 b...
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