- Synthesis of radioiodinated probes targeted toward matrix metalloproteinase-12
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Matrix metalloproteinase-12 (MMP-12, macrophage elastase) is a member of the MMP family that is responsible for the degradation of extracellular matrix, and is associated with the inflammatory process of chronic obstructive pulmonary disease (COPD). COPD, characterized by progressive and irreversible airflow obstruction, is recently a major cause of mortality and morbidity worldwide. Herein, to develop radioiodinated probes for the early diagnosis of COPD, we designed and synthesized novel MMP-12-targeted dibenzofuran compounds (1–3) with a variety of linker structures (carbamate, amide, and sulfonamide). In competitive enzyme activity assays, it was revealed that the linker structures significantly affected the inhibitory activity against and selectivity for MMP-12. Compound 1, with carbamate linker, demonstrated potent MMP-12 inhibitory activity (IC50 = 8.5 nM) compared to compound 2, with amide linker, and compound 3, with sulfonamide linker. Using bromo-substituted carbamate 13 as a radioiodination precursor, [125I]1 was successfully prepared to high radiochemical purity (over 98%) and good specific radioactivity (4.1 GBq/μmol). These results suggest that radioiodinated compound 1 is potent as a novel MMP-12-targeted probe.
- Hagimori, Masayori,Temma, Takashi,Kudo, Shinji,Sano, Kohei,Kondo, Naoya,Mukai, Takahiro
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supporting information
p. 193 - 195
(2017/12/04)
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- Discovery of potent and selective matrix metalloprotease 12 inhibitors for the potential treatment of chronic obstructive pulmonary disease (COPD)
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Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with irreversible progressive airflow limitation. Matrix metalloproteinase-12 (MMP-12) has been characterized to be one of the major proteolytic enzymes to induce airway remodeling, destruction of elastin and the aberrant remodeling of damaged alveoli in COPD and asthma. The goal of this project is to develop and identify an orally potent and selective small molecule inhibitor of MMP-12 for treatment of COPD and asthma. Syntheses and structure-activity relationship (SAR) studies of a series of dibenzofuran (DBF) sulfonamides as MMP-12 inhibitors are described. Potent inhibitors of MMP-12 with excellent selectivity against other MMPs were identified. Compound 26 (MMP118), which exhibits excellent oral efficacy in the MMP-12 induced ear-swelling inflammation and lung inflammation mouse models, had been successfully advanced into Development Track status.
- Wu, Yuchuan,Li, Jianchang,Wu, Junjun,Morgan, Paul,Xu, Xin,Rancati, Fabio,Vallese, Stefania,Raveglia, Luca,Hotchandani, Rajeev,Fuller, Nathan,Bard, Joel,Cunningham, Kristina,Fish, Susan,Krykbaev, Rustem,Tam, Steve,Goldman, Samuel J.,Williams, Cara,Mansour, Tarek S.,Saiah, Eddine,Sypek, Joseph,Li, Wei
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p. 138 - 143
(2012/02/16)
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- TRICYCLIC COMPOUNDS AS MATRIX METALLOPROTEINASE INHIBITORS
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The present teachings relate to compounds of formula I: and pharmaceutically acceptable salts and esters thereof, wherein R1, R2, R3, R4, X, and Y are as defined herein. The present teachings also provide methods of making the compounds of formula I and methods of inhibiting matrix metalloproteinases, in particular, MMP-12, that may be involved in pathological disorders found in mammals, including a human.
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Page/Page column 63-64
(2010/09/17)
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- A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): Discovery of (S)- 2-(8-(Methoxycarbonylamino)dibenzo[b,d]furan- 3-sulfonamido)-3-methylbutanoic acid (MMP408)
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Matrix metalloprotease 12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been found in the lung of human COPD patients. MMP408 (14), a potent and selective MMP-12 inhibitor, was derived from a potent matrix metalloprotease 2 and 13 inhibitor via lead optimization and has good physical properties and bioavailability. The compound blocks rhMMP-12-induced lung inflammation in a mouse model and was advanced for further development for the treatment of COPD.
- Wei, Li,Jianchang, Li,Yuchuan, Wu,Junjun, Wu,Hotchandani, Rajeev,Cunningham, Kristina,McFadyen, Iain,Bard, Joel,Morgan, Paul,Schlerman, Franklin,Xin, Xu,Tam, Steve,Goldman, Samuel J.,Williams, Cara,Sypek, Joseph,Mansour, Tarek S.
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supporting information; experimental part
p. 1799 - 1802
(2009/12/07)
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- TRICYCLIC COMPOUNDS AS MATRIX METALLOPROTEINASE INHIBITORS
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The present invention relates to compositions of the formula (I): and pharmaceutically acceptable salts, hydrates, or esters thereof, wherein R1, R2, R3, R4, R5, X, and Y are as defined herein. The present teachings also provide methods of making the compounds of formula I, and methods of treating pathologic conditions or disorders mediated wholly or in part by matrix metalloproteinases, such as asthma and chronic obstructive pulmonary disease, comprising administering a therapeutically effective amount of a compound of formula (I) to a mammal (e.g., a human) in need thereof.
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Page/Page column 73
(2008/12/05)
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- Synthesis and biological activity of various derivatives of a novel class of potent, selective, and orally active prostaglandin D2 receptor antagonists. 1. Bicyclo[2.2.1]heptane derivatives
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Novel prostaglandin D2 (PGD2) receptor antagonists were synthesized as a potential new class of antiallergic agents having a bicyclo[2.2.1] heptane ring system with sulfonamide groups. Some of them exhibit extremely potent antagonism of the PGD2 receptor in radioligand binding and cAMP formation assays with IC50 values below 50 nM and much less antagonism of TXA2 and PGI2 receptors. These potent PGD2 receptor antagonists, when given orally, dramatically suppress various allergic inflammatory responses such as increased vascular permeability in allergic rhinitis, conjunctivitis, and asthma models. The excellent pharmacological profiles of PGD2 receptor antagonists, originally synthesized in our laboratories, are of potentially great clinical significance. This study also provides experimental evidence suggesting that PGD2 plays an important role in the pathogenesis of allergic diseases.
- Mitsumori, Susumu,Honma, Tsunetoshi,Tsuri, Tatsuo,Hiramatsu, Yoshiharu,Okada, Toshihiko,Hashizume, Hiroshi,Inagaki, Masanao,Arimura, Akinori,Yasui, Kiyoshi,Asanuma, Fujio,Kishino, Junji,Ohtani, Mitsuaki
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p. 2436 - 2445
(2007/10/03)
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- Dibenzofuran sulfonamide matrix metalloproteinase inhibitors
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The present invention relates to compounds of Formula I that inhibit matrix metalloproteinases and to a method of inhibiting matrix metalloproteinases using the compounds. wherein Q is an un-natural amino acid. More particurlarly, the present invention re
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