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CONJUGATED VASOACTIVE AGENTS AS A NEW CLASS OF DRUGS

共轭血管活性剂作为一类新的药物

基本信息

批准号：
3338576
负责人：
KENNETH L MELMON
金额：
$ 56.89万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1980
资助国家：
美国
起止时间：
1980-07-01 至 1986-06-30
项目状态：
已结题

项目摘要

The clinical utility of a number of cardiovascular drugs particularly vasoactive amines, is limited by their widespread distribution and effects. In the last two years, we have extended preliminary observations made by ourselves and others that congeners and congener derivatives of betamimetic catecholamines and beta blockers can be synthesized to serve as pharmacophores for covalent linkage to uniform peptide or protein carriers to construct fully pharmacologically and chemically characterizable drug conjugates. The congeners, congener derivatives and conjugates may be more potent, more efficacious and longer acting in vitro and in vivo than the parent drug. They may have apparent receptor and tissue specific effects that differ in key physical and pharmacological ways from the parent. Furthermore, they may be active when given by routes (e.g., oral administration) which were ineffective for the parent compounds. Based on these phenomenologic observations, we propose to: 1) study the mechanisms (molecular, physical, chemical, pharmacologic, metabolic and/or pharmacokinetic) that explain the variant effects of parent compounds from key congeners and/or conjugates and the variant effects seen in vitro versus in vivo by the same compound; 2) economically determine the changes in potency and efficacy of further systematic chemical alterations of the conjugates; 3) determine whether oligopeptide, monoclonal antibody or other monodisperse protein carriers, linked to different combinations of pharmacophores, can be key determinants of tissue and/or receptor specific events caused by the conjugates; and 4) continue to make compounds available for others interested in the use of these agents as probes to understand the molecular mechanisms of drug effects in tissues or who wish to capitalize on the apparent or real tissue or effect specificity already seen in two chemicals that make them very suitable as potential drugs for man.

一些心血管药物的临床效用，特别是血管活性胺，受到其广泛分布的限制，方面的影响. 在过去的两年里，我们已经扩大了初步观察，由我们自己和其他人制造，可以合成β-拟儿茶酚胺和β-阻滞剂，用于共价连接至均一肽或蛋白质载体的药效团构建完全可生物降解的化学表征药物，结合物。同源物、同源物衍生物和缀合物可能更多在体外和体内，母体药物。它们可能具有明显的受体和组织特异性作用在关键的物理和药理学方面与母体不同。此外，当由路由给出时，它们可以是活动的（例如，口服给药），其对母体化合物无效。基于这些现象学的观察，我们建议：1）研究机制（分子、物理、化学、药理学、代谢和/或药代动力学），其解释了母体化合物的不同作用，关键同系物和/或结合物以及体外观察到的变异效应与体内相同的化合物; 2）经济地确定变化进一步系统性化学改变的效力和功效 3）确定寡肽、单克隆抗体或其它缀合物是否与肽缀合; 单分散蛋白载体，连接到不同的组合，药效团，可以是组织和/或受体特异性的关键决定因素。由缀合物引起的事件;以及4）继续制造化合物可供其他有兴趣使用这些代理作为探针，了解药物在组织中作用的分子机制，或者希望利用表面或真实的组织或效应特异性这两种化学物质使它们非常适合作为潜在的药物，伙计