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Dual Purpose b-Lactamase Inhibitors

双重用途 β-内酰胺酶抑制剂

基本信息

批准号：
6736701
负责人：
JOHN D BUYNAK
金额：
$ 13.72万
依托单位：
DESIGN THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2007-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6736701
关键词：
beta lactam antibiotic chemical synthesis combinatorial chemistry drug design /synthesis /production drug resistance enzyme inhibitors lactams metalloenzyme

项目摘要

DESCRIPTION (provided by applicant): The ability to produce one or more b-lactamases represents the most common form of bacterial resistance to the b-lactam antibiotics. One successful method of countering such resistance is the co-administration of a b-lactam antibiotic and a b-lactamase inhibitor. Historically, such combination products have been both efficacious and commercially successful. However, despite the rising clinical incidence of class B (metallo) and classes C and D (serine) b-lactamases, current commercial b-lactamase inhibitors narrowly target the class A (serine) enzymes. Our research group has recently reported efficacious new inhibitors of the serine b-lactamases. These compounds are not only superior to the best commercially available inhibitors of the class A b-lactamases, but are also simultaneously effective against class C and class D enzymes. The current proposal involves a new class compounds, selected example of which have already been synthesized and already proven to be effective inhibitors of both class B metallo-b-lactamases as well as one or more of the serine classes. These compounds were designed by taking advantage of the similar substrate specificity of the metallo and serine-b-lactamases (i.e. the specificity to hydrolyze appropriately substituted bicyclic b-lactams). Thus, these compounds are mechanism based inhibitors of both serine and metallo-b-lactamases and are the first reported penicillin-derived inhibitors of the metallo-b-lactamases. These new inhibitors fill an important scientific and commercial gap, allowing for the first time, potential commercialization of a class B (metallo) b-lactamase inhibitor. Therefore, we now propose the further development of this class of compounds into a viable pharmaceutical product. Synthetic methodology has already been developed to facilitate the preparation of more examples of this class of molecules. A group of scientists, including chemists, microbiologists, enzymologists, and crystallographers has been assembled to allow rapid optimization of SAR.

描述（由申请人提供）：产生一种或多种b-内酰胺酶的能力代表了细菌对b-内酰胺类抗生素耐药的最常见形式。对抗这种耐药性的一种成功方法是b-内酰胺类抗生素和b-内酰胺酶抑制剂的联合施用。从历史上看，这种组合产品既有效又在商业上取得了成功。然而，尽管B类（金属）、C类和D类（丝氨酸）B -内酰胺酶的临床发病率不断上升，但目前商业化的B -内酰胺酶抑制剂仅针对A类（丝氨酸）酶。我们的研究小组最近报道了有效的新的丝氨酸b-内酰胺酶抑制剂。这些化合物不仅优于市面上最好的A类b-内酰胺酶抑制剂，而且对C类和D类酶同时有效。目前的建议涉及一类新的化合物，其中选择的例子已经合成并已被证明是B类金属- B -内酰胺酶以及一种或多种丝氨酸类的有效抑制剂。这些化合物是利用金属酶和丝氨酸-b-内酰胺酶相似的底物特异性（即水解适当取代的双环b-内酰胺的特异性）设计的。因此，这些化合物是丝氨酸和金属-b-内酰胺酶的基于机制的抑制剂，并且是首次报道的青霉素衍生的金属-b-内酰胺酶抑制剂。这些新的抑制剂填补了重要的科学和商业空白，首次允许B类（金属）B -内酰胺酶抑制剂的潜在商业化。因此，我们现在建议进一步将这类化合物开发成可行的药物产品。已经发展了合成方法，以方便制备更多这类分子的例子。一组科学家，包括化学家，微生物学家，酶学家和晶体学家已经集合，以允许快速优化SAR。