Synthesis of Libraries of Statine Analogues

描述(申请人提供)：他汀类药物及其类似物代表了一类关键的药物中间体，适用于多种适应症。目前，这些化合物中只有两种是他汀类和苯基他汀类，在四种可能的非对映异构体中，只提供了(3S，4S)和(3R，4S)形式。此外，目前每克1000美元以上的价格如此之高，以至于将这些重要的中间体纳入开发药物候选药物受到了限制。在这个第一阶段的提案中，我们试图建立一种简单的两步化学-酶法来合成所有可能的非对映异构体形式的他汀类类似物的文库。在第一步中，将使用我们实验室成熟的化学方法将α-氨基酸同源化为相应的β-酮类他汀类化合物。第二步是用酮还原酶对酮进行立体选择性还原。我们将对我们实验室克隆、过度表达和生产的10种或更多广谱的酮还原酶进行筛选，以检测对至少10种不同的β-酮他汀类类似物的活性，并将通过生产至少3种不同的克级他汀类类似物来证明该方法的可行性。这种方法如果成功，将使大量他汀类类似物以显著较低的成本容易获得。

DESCRIPTION (provided by applicant): Statine and its analogs represent a key class of intermediates for drug spanning a wide range of indications. Presently, only two of these compounds, statine and phenylstatine, are commercially available, and of the four possible diastereomers, only the (3S,4S) and (3R,4S) forms are offered. Furthermore, current prices of more than $1000 per gram are so high that incorporation of these important intermediates into developmental drug candidates is inhibited. In this Phase 1 proposal we seek to establish a simple two-step chemo-enzymatic method for the synthesis of a library of statine analogues in all possible diastereomeric forms. In the first step, homologation of alpha-amino acids into the corresponding beta-keto statine analogues will be achieved using chemical methodology that has been well-established in our laboratory. Stereoselective reduction of the ketone using ketoreductase enzymes is the second step. Ten or more broad range ketoreductases that have been cloned, over-expressed, and produced in our laboratories will be screened for activity against at least ten different beta-keto statine analogues, and the feasibility of the method will be proven by producing at least three different statine analogs at the gram scale. This method, if successful, will make a wide range of statine analogues readily available at significantly lower cost.