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Prinomastat

About: Prinomastat is a research topic. Over the lifetime, 57 publications have been published within this topic receiving 6032 citations. The topic is also known as: AG-3340.


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Journal Article
TL;DR: Agouron Pharmaceuticals is developing AG-3340 (prinomastat), the lead compound in a series of structurally related metalloproteinase inhibitors, for the potential treatment of cancer and age-related macular degeneration, which has demonstrated significant antimetastatic and antitumor activity in animal models and oral bioavailability and a favorable pharmacokinetic profile.
Abstract: Agouron Pharmaceuticals is developing AG-3340 (prinomastat), the lead compound in a series of structurally related metalloproteinase inhibitors, for the potential treatment of cancer and age-related macular degeneration. AG-3340, an oral, non-peptide inhibitor of gelatinase types A and B (MMP-2 and -9), MT1-MP (MMP-14) and collagenase III [234058], was selected following demonstration of activity in a variety of in vivo preclinical models upon oral dosing. In May 1999, phase III trials for lung and prostate cancers of AG-3340 in front-line combination with chemotherapy was begun in the US and Canada [286380,326640]. The tested dose for these trials is 5 to 15 mg bid. Following demonstration of the enhanced efficacy of chemotherapy when supplemented with AG-3340 in preclinical tumor models, pilot combination studies and double-blinded, placebo-controlled phase III trials in 700 patients are in progress for the treatment of non-small cell lung cancer or advanced hormone-refractory prostate cancer [302584,327014]. In August 1999, Agouron initiated a second, confirmatory phase III trial of AG-3340 in combination with chemotherapy in patients with advanced non-small cell lung cancer [337253]. Pharmacokinetic studies have been conducted in healthy male volunteers and single agent dose-escalation studies in patients demonstrated toxicities (grade 1 or 2; joint related) were not doselimiting [302238]. At the 10th European Organization for Research and Treatment of Cancer (EORTC) meeting in Amsterdam (June 1998), Agouron released encouraging results from two phase I studies and one preclinical study of AG-3340 [289688]. In a further 15- patient, phase I study of AG-3340 with paclitaxel and carboplatin, the combination was safe and well tolerated [326268]. AG-3340 has demonstrated significant antimetastatic and antitumor activity in animal models, as well as oral bioavailability and a favorable pharmacokinetic profile. Daily doses of 50 mg/kg completely halted growth of Lewis lung carcinomas in two thirds of test animals and reduced the formation of lung metastasis (0.5 mm in diameter) by 90% [205708]. In December 1997, Roche announced it would discontinue its cancer R&D collaborations with Agouron on AG-3340 as it did not fulfill its scientific and business objectives [271723]. Agouron is investigating analogs of AG-3340 which are undergoing animal studies [332841].

8 citations

Patent
28 Jul 2006
TL;DR: In this paper, the authors proposed a method for treating a fatty liver disease or disorder in a patient in need thereof, which comprises administering at least one matrix metalloproteinase ('MMP') inhibitor to the patient.
Abstract: The present invention relates to a method for treating a fatty liver disease or disorder in a patient in need thereof. The method comprises administering at least one matrix metalloproteinase ('MMP') inhibitor to the patient. Fatty liver disease or disorders include, for example, NAFLD, NASH, ALD, fatty liver associated with chronic hepatitis infection, TPN, steroid treatment, tamoxifen treatment, gastrointestional operations, diabetes and Reye's Syndrome. The method is particularly useful when the fatty liver disease is associated with TPN and the patient is an infant or when the patient is obese. MMP inhibitors useful in the present invention include, for example, Marimastat, tetracyclines, Prinomastat, Batimastat, BAY 12-9566, AG3340 , BMS-275291, Neovastat , BB-3644, KB-R7785, TIMPl, TIMP2, doxycycline, minocycline, RS-130,830; CGS 27023A, Solimastat, Ro 32-3555, BMS-272591, and D2163. Marimastat is a preferred MMP inhibitor.

6 citations

Journal ArticleDOI
TL;DR: It is demonstrated that prinomastat delivery from β-cyclodextrin polymers results in months-long inhibition of MMPs as measured by gelatin zymography, more appropriately addressing the time frame of cancer cell invasion.
Abstract: Glioblastoma multiforme patients suffer a median survival of 14 months, facilitated by the highly invasive nature of this cancer that allows for it to evade conventional therapy. Prinomastat targets the essential matrix metalloproteinase degradation of the extracellular matrix needed for cancer invasion; however, its clinical potential is impeded by adverse musculoskeletal side effects. By localizing delivery of prinomastat via cyclodextrin polymers, systemic side effects can be bypassed. In this letter, we demonstrate that prinomastat delivery from β-cyclodextrin polymers results in months-long inhibition of MMPs as measured by gelatin zymography, more appropriately addressing the time frame of cancer cell invasion.

5 citations

Patent
28 Jul 2006
TL;DR: In this article, a method for treating a fatty liver disease or disorder in a patient in need thereof is proposed, which comprises administering at least one matrix metalloproteinase (MMP) inhibitor to the patient.
Abstract: The present invention relates to a method for treating a fatty liver disease or disorder in a patient in need thereof. The method comprises administering at least one matrix metalloproteinase (“MMP”) inhibitor to the patient. Fatty liver disease or disorders include, for example, NAFLD, NASH, ALD, fatty liver associated with chronic hepatitis infection, TPN, steroid treatment, tamoxifen treatment, gastrointestional operations, diabetes and Reye's Syndrome. The method is particularly useful when the fatty liver disease is associated with TPN and the patient is an infant or when the patient is obese. MMP inhibitors useful in the present invention include, for example, Marimastat, tetracyclines, Prinomastat, Batimastat, BAY 12-9566, AG3340, BMS-275291, Neovastat, BB-3644, KB-R7785, TIMP1, TIMP2, doxycycline, minocycline, RS-130,830; CGS 27023A, Solimastat, Ro 32-3555, BMS-272591, and D2163. Marimastat is a preferred MMP inhibitor.

5 citations

Book ChapterDOI
01 Jan 2002
TL;DR: Two important approaches to the design, synthesis, and biological evaluation of MMPIs are highlighted: the invention of alternatives to hydroxamic acid zinc chelators and the construction of nonpeptide scaffolds.
Abstract: Matrix metalloproteinases (MMPs) are involved in extracellular matrix degradation. Their proteolytic activity must be precisely regulated by their endogenous protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Experimental evidence confirms that MMPs play a decisive role in a wide variety of pathologic conditions that involve connective tissue destruction such as arthritis, tumor growth and metastasis. Modulation of MMP regulation is possible at several biochemical sites, but direct inhibition of enzyme action provides a particularly attractive target for therapeutic intervention. To date the main focus of the therapeutic applications of MMP inhibitors (MMPIs) has been in the areas of cancer and arthritis. One key issue in their clinical development relates to whether broad spectrum inhibitors, active against a range of different enzymes, or selective inhibitors targeted against a particular subset of the MMPs, represents the optimal strategy. Some orally active compounds for the treatment of cancer and/or arthritis are currently under clinical investigations. Representative examples include succinamides (Marimastat), linear sulfonamides (CGS-27023A), heterocyclic sulfonamides (Prinomastat) and biphenylbutyric acid derivatives (BAY-129566). However, since their inception during the eighties, MMPIs have gone through several cycles of metamorphosis. From this, two important approaches to the design, synthesis, and biological evaluation of MMPIs are highlighted: 1. the invention of alternatives to hydroxamic acid zinc chelators and 2. the construction of nonpeptide scaffolds. One current example from our own work in each of these two approaches is described.

3 citations

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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
20211
20201
20171
20132
20123
20101