摘要:

The mature extracellular matrix (ECM) is a heterogenous substance produced by a variety of cells, mostly of mesothelial origin. The ECM serves as a tissue skeleton, a medium of communication between cells and as a barrier between the cells and the vascular system. The matrix is continuously remodelled in the living tissues. A variety of proteases, including matrix metalloproteases (MMPs), contribute to matrix destruction. These proteases are neutralised by naturally occurring inhibitors such as &agr;2-macroglobulin or tissue inhibitors of metalloproteases (TIMPs). Proteases and their inhibitors are often produced by the same cells, thus matrix remodelling is localised and strictly controlled.The MMPs are zinc-endopeptidases functioning at a neutral pH and requiring ionised calcium for activity. The extracellular matrix is an essential part of every organ and tissue type. MMPs are the key components of the system that dynamically controls the structure and function of the ECM. MMPs have been implicated in corneal disease, periodontal disease, dermatological disorders, atherosclerosis, bone and joint disorders, fibrotic disease, vascular abnormalities, malignancy and many other pathological processes.Several synthetic inhibitors of MMPs have been developed and many of them are currently in clinical trials. Compounds discussed in this article include batimastat, marimastat, BAY12-9566, AG-3340, OPB-3206, KBR-7785, KBR-8301, CDP-845 (CT-1746), metastat and AE-941 (Neovastat®).

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

All the drugs appearing in the Adis Profile Summary table have been selected based on information contained inR&D InsightTM, a proprietary product of Adis International. As the emphasis ofDrugs in R&Dis on the clinical potential of new drugs, selection of agents for a full profile is based on the extensiveness of available data. Information on all drugs in clinical development, as identified fromR&D InsightTM, is included in the summary table. Information and/or profiles of agents in preclinical development may be included as appropriate.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

AE 941 is shark cartilage extract which inhibits angiogenesis. It is being developed by AEterna Laboratories in Canada as NeovastatTMfor the treatment of cancer. Phase I/II Canadian and US trials of NeovastatTMhave been completed for the treatment of refractory lung cancer (n = 80) and are ongoing for the treatment of breast and prostate cancers. AEterna has signed a Clinical Trials Agreement (CTA) with the National Carter Institute (NCI) for the realisation of a pivotal phase III clinical trial of AE 941 for the treatment of non-small-cell lung cancer in combination with chemo/radiotherapy. The trial is expected to begin in the second quarter of 1999 and will enrol over 550 patients in the US and Canada. AEterna Laboratories has agreed to a limited distribution of AE 941 to Canadian doctors who request it from the Health Protection Branch for the treatment of patients with refractory conditions. AE 941 is also being developed for other indications by AEterna.AE 941 is the first anticancer agent derived from shark cartilage to demonstrate efficacy without serious adverse events in patients with solid tumours. AE 941 is a promising drug candidate as a first-line treatment for cancer in combination with current therapy.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

AG 3340 is an orally available, lead compound selected from a series of highly selective, nonpeptidic matrix metalloprotease inhibitors (MMPIs) developed by researchers at Agouron Pharmaceuticals, USA. The drug has also inhibited angiogenesis in animal studies. Agouron has inititated 2 North American phase II/III pivotal clinical trials for the treatment of advanced non-smallcell lung (n = 500 in combination with paclitaxel and carboplatin) and advanced prostate cancer (n = 500 in combination with mitoxantrone and prednisone). Another trial in non-small-cell lung cancer in combination with cisplatin/etoposide is planned.In September 1998, Agouron intiated a phase II trial to evaluate the efficacy and tolerablity of AG 3340 when used to treat age-related macular degeneration. The US trial will involve approximately 100 patients over the age of 50 years. Preclinical studies have shown that AG 3340 can cross the blood-retina barrier.In addition, AG 3340 is in phase I clinical development as an antirheumatic agent. Roche Bioscience has marketing rights for the indication of rheumatic disease.AG 3340 is the first in a series of MMPIs with potential in the treatment of both solid tumours and age-related macular degeneration. Its positive features include oral administration and linear kinetics. Its relative lack of potency against collegenase 1, compared with gelatinases and stromelysin 1, is expected to result in fewer serious adverse events compared with non-selective MMPIs. No serious adverse events have been seen in cancer patients to date.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;Batimastat is a synthetic low molecular weight (474Da) broad-spectrum collagenase and matrix metalloprotease inhibitor (MMPI) originally synthesised by British Biotech. Batimastat is the lead compound of this class which also includes another hydroxamate MMPI, BB 2516. Unlike most cancer therapies, batimastat is designed to prevent malignant cells from breaking away to form secondary tumours rather than eradicating all cells from the body. It is also designed to ‘starve’ tumours of nutrients by inhibiting the development of blood vessels. Native MMPIs also exist (TIMP-1, TIMP-2) although these are disadvantaged by lack of oral activity. Batimastat is undergoing phase II clinical trials in the UK for the treatment of pleural effusions. Pivotal phase III clinical trials of batimastat in the treatment of malignant ascites were suspended by British Biotech following unexpected adverse effects (inflammation and pain in the abdomen) among patients. However, although UK approval was granted for clinical trials to recommence with a dose-ranging study, British Biotech has since discontinued clinical development of batimastat for the treatment of malignant ascites.Batimastat is the lead synthetic broad-spectrum MMPI. It had shown promising activity in phase I studies against malignant ascites, however development was discontinued due to severe adverse effects.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

BAY12-9566 inhibits angiogenesis and matrix metalloproteases. Developed by Bayer, it is undergoing phase III comparative trials in the USA for the treatment of non-small-cell lung, small-cell lung and pancreatic cancer (900 patients in each trial). The National Institute of Canada's Clinical Trials Group has initiated an international phase III trial for the treatment of patients with advanced ovarian cancer (n = 900) who have responded positively to 6 to 8 cycles of standard chemotherapy after surgery. The study's primary objective is to determine the drug's effectiveness in keeping patients in remission. The study will take place in Canada, Europe, South Africa and Israel.BAY12-9566 is also being investigated for the treatment of osteoarthritis. Development for this indication appears to be at the phase I stage in the US.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;CGS 27023A is a nonpeptide matrix metalloprotease inhibitor which is showing potential in phase I studies as a therapy for solid tumours, and in preclinical studies as a therapy for osteoarthritis and rheumatoid arthritis. It is undergoing phase I studies with Novartis for the treatment of solid tumours in the UK, the Netherlands and Switzerland. CGS 27023A appears well to be tolerated at doses greater than 300mg twice daily, with biologically relevant plasma levels. No tumour regressions have been observed to date.It has been developed by Novartis to target the matrix metalloprotease stromelysin, which is found in elevated levels in cartilage and synovial fluid of patients with osteoarthritis. Novartis has selected the compound as a candidate for clinical development for osteoarthritis and rheumatoid arthritis.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;Marimastat is a second generation anticancer drug that is being developed with British Biotech in Europe and North America. It is an orally active metalloprotease inhibitor of the same class as batimastat. Marimastat also has collagenase and angiogenesis inhibiting properties.Marimastat is in pivotal phase III trials in glioblastoma (recruitment complete), pancreatic (n = 400, recruitment complete), small cell lung (recruitment complete), non-small-cell lung (n = 500), gastric (n = 360, recruitment complete) and ovarian cancers. In these trials marimastat is being compared with standard chemotherapy or placebo. British Biotech will be continuing the pancreatic cancer trial following the unauthorised unblinding of the trial. In addition, marimastat is in a phase III trial in pancreatic cancer in combination with gemcitabine (recruitment phase complete), and in a phase III ovarian cancer trial in combination with carboplatin. A further trial is underway for the adjuvant therapy of patients who have had their pancreatic cancer removed by surgery (n = 500). Two additional phase III trials are being conducted by external cooperative oncology groups in metastatic breast cancer (US) and small cell lung cancer (Europe and Canada). Discussions are underway to increase patient numbers in the small-cell lung cancer trial from 360 to 540.British Biotech is seeking a strategic alliance to advance development of marimastat and assist in obtaining regulatory approval and commercialisation in the USA and Europe.Marimastat is licensed to Tanabe Seiyaku in Japan, where phase II clinical trials are underway for the treatment of advanced gastric cancer and lung cancer, further phase II trials in other tumour types are planned. The commencement of phase II trials in Japan resulted in a milestone payment to British Biotech from Tanabe.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

With the increase in serious and often life-threatening fungal infections over the last 2 decades, there has been an enhanced effort to bring new antifungal agents into the therapeutic armamentarium. The introduction of new agents into the clinical setting has been slow, in part because several drugs which appeared promisingin vitroand in short term animal studies later proved to be toxic.Toxicity has been a major hurdle in the development of antifungal agents because mammalian cells, in contrast to bacterial cells, share with fungal cells many structures and metabolic pathways. For example, the 2 most common classes of antifungal agents, polyenes and azoles, target the synthesis of the cell membrane, a structure shared by both mammalian and fungal cells, and thus these drugs have inherent toxicity. Antifungal agents that act on protein synthesis are also inherently toxic to mammalian as well as fungal cells. New agents that target the fungal cell wall, a structure with no homology in mammalian cells, may prove to be less toxic and are currently of great interest.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

All the drugs appearing in the Adis Profile Summary table have been selected based on information contained inR&D InsightTM, a proprietary product of Adis International. As the emphasis ofDrugs in R&Dis on the clinical potential of new drugs, selection of agents for a full profile is based on the extensiveness of available data. Information on all drugs in clinical development, as identified fromR&D InsightTM, is included in the summary table. Information and/or profiles of agents in preclinical development may be included as appropriate.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS