摘要:

Since its discovery in 1988, endothelin (ET) has been widely implicated in the pathophysiology of cardiovascular disease. ET antagonists have favourable effects in experimental models of these conditions and have proved useful in elucidating the role of the ET system. Orally acting ET antagonists appear very promising in clinical trials, particularly in patients with chronic heart failure and hypertension, but more information on the roles of the ET receptor subtypes in health and disease is required so that an informed choice can be made between the use of endothelin-A (ET-A) receptor?selective and nonselective receptor antagonists.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

All 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 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:

&NA;ABT 627 (A147627, ABT 147627) is a selective endothelin-A (ET-A) antagonist. It is the active enantiomer of the racemate, A127722. It is about 1000-fold selective for the ET-A versus endothelin-B receptor.ABT 627 is undergoing phase I clinical trials in the US for the treatment of coronary disorders and refractory adenocarcinomas and phase II trials for prostate cancer. It may have potential in the prevention and/or treatment of coronary restenosis after percutaneous revascularisation with stents.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;Bosentan (RO 470203), a sulfonamide, is a competitive endothelin (ET) receptor antagonist that antagonises both endothelin-A (ET-A) and endothelin-B (ET-B) receptors. Bosentan is derived fromRO462005 andwas undergoing phase III investigation with Roche in Switzerland for disorders associated with vasoconstriction. A phase III, multicentre trial for congestive heart failure (CHF) [REACH-1 trial] was terminated early as a result of liver toxicity at high doses. Development was suspended while Roche was seeking a development partner for bosentan. Actelion, a Swiss research company, has partnered with Roche for the development of bosentan in the treatment and/or prevention of diseases relating to the vascular endothelium. Actelion is planning to initiate a large phase III trial in patientswithCHF during the second quarter 1999. TheREACH-II trial is being conducted at the University of Alberta, Canada. The agreement between Roche and Actelion allows Roche to reclaim development of bosentan after completion ofActelion's phase III trial. The trialwill be investigating lower doses of bosentan than the original REACH-1 trial, and will involve a teamof liver function experts.Bosentan appears to be in clinical investigation for ischaemic heart disorders.Researchers at the Kagawa Medical University in Japan are preclinically investigating the effects of bosentan in the prevention of reperfusion injury in animals undergoing heart transplant.Researchers at St Vincent's Hospital in Australia are preclinically investigating bosentan as a treatment for prevention of chronic allograft rejection for aortic transplantation.Bosentan, a competitive ET antagonist, represents a novel therapeutical approach, since there is an evidence that ET may contribute to hypertension and associated cardiovascular disorders. Orally bioavailable bosentan is suitable for once daily administration in hypertension, with efficacy similar to that of enalapril. In CHF, a twice daily dose has been used in trials. Bosentan is well tolerated. The reported adverse events are associated with high doses of the drug.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

Enrasentan (SB 217242), an orally active, nonselective endothelin-A/B receptor antagonist, is in phase II trials in the US with SmithKline Beecham for pulmonary hypertension secondary to chronic obstructive pulmonary disease. Enrasentan is also in phase I trials for the treatment of congestive heart failure and undergoing preclinical investigation with SmithKline Beechamin theUS and Canada for the treatment of stroke, chronic renal failure and for prevention of reperfusion injury causing restenosis after percutaneous transluminal coronary angioplasty.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;J 104132 (L 753037), a pyridine carboxylic acid derivative, is an orally active mixed endothelin-A/B receptor antagonist under phase I clinical development with Banyu and Merck Research Laboratories (both Merck & Co.) in the US. It may have potential in the treatment of hypertensive patients who do not respond adequately to ACE inhibitors or angiotensin II receptor antagonists.J 104132 is also being investigated in preclinical studies in the US as a potential therapy in the treatment of heart failure.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;LU 135252 (HMR4005), a selective endothelin-A(ET-A) receptor antagonist, is the active enantiomer of LU 127043. It is undergoing phase II development with Knoll (BASF) in Europe for the treatment of congestive heart failure (CHF) and hypertension. LU 135252 may also have potential in the treatment of pulmonary hypertension secondary to CHF.Preclinical results indicate that the agent has antiarrhythmic activity. Reports of preclinical investigation in other aspects of cardiovascular therapy have been published, but development is not proceeding.Knoll andHoechstMarionRoussel have entered into an alliance to codevelop LU 135252 for chronic heart failure and hypertension. Both companies have also agreed to an option to jointly commercialise the product pending the completion of development and regulatory approval of the product. Both companies will share the development costs. In addition, Hoechst Marion Roussel will pay Knoll milestone payments and royalties.LU 135252, an orally active and selective ET-A receptor antagonist, has potential in the treatment of ischaemic heart disease, acute ischaemic stroke, CHF and hypertension. In animal studies, pretreatment with LU 135252 completely prevented endothelin-induced sudden death, reduced BP, neotiminal formation and infarct size. The relative oral efficacy of LU 135252 was superior to that of bosentan.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

RO 610612, a combined endothelin-A and -B antagonist, is in development with Actelion in the US and Europe. Actelion has an exclusive worldwide license for RO 610612 from Roche, but Roche has the right of first refusal to license it back once phase II trials have been completed. RO 610612 is in phase II trials and may have potential in acute haemodynamic conditions including hypertension, heart failure and other cardiovascular disorders. It may also have potential in the prevention of reperfusion injury associated with organ transplantation for which preclinical investigations are being carried out in the US.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;TA0201 (T 0201), an orally active, selective endothelin-Areceptor antagonist, is a derivative of TA0115 and is under development by Tanabe Seiyaku in Japan. It may have potential in the treatment of heart failure and is in phase I clinical investigation. It is also in preclinical investigation in pulmonary hypertension and reperfusion injury.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS

摘要:

&NA;TAK 044, an endothelin-A (ET-A) and -B antagonist, is in phase II clinical trials with Takeda in Japan for acute myocardial infarction (MI) and ischaemic hepatic dysfunction following surgery. It is also in phase II trials in the US for MI and is in phase I clinical trials in the UK for the treatment of MI. TAK 044 was also in phase I clinical trials in the UK, and under clinical investigation in other countries in Europe for the treatment of hypertension. However, there is no recent data reported for this indication. In addition, TAK 044 is in phase II trials for acute renal failure and subarachnoid haemorrhage in Europe. Preclinical investigation of TAK 044 in congestive heart failure has been reported from the Shiga University of Medical Science in Japan.

ISSN:1174-5886    

出版商:ADIS    

年代:1999

数据来源: ADIS