Synthesis of Libraries of Statine Analogues

描述（由申请人提供）：他汀及其类似物是一种关键的药物中间体，适用于广泛的适应症。目前，这些化合物中只有两种，他汀和苯基他汀，是可商购的，并且在四种可能的非对映异构体中，仅提供（3S，4S）和（3R，4S）形式。此外，目前每克超过1000美元的价格是如此之高，以至于这些重要的中间体掺入开发药物候选物受到抑制。在这个阶段1的建议，我们试图建立一个简单的两步化学-酶法合成库的他汀类似物在所有可能的非对映体形式。在第一步中，将使用我们实验室中已确立的化学方法将α-氨基酸同源化为相应的β-酮他汀类似物。第二步是使用酮还原酶对酮进行立体选择性还原。我们将筛选在我们实验室中克隆、过表达和生产的10种或更多种广泛的酮还原酶对至少10种不同的β-酮他汀类似物的活性，并将通过生产至少3种不同的克级他汀类似物来证明该方法的可行性。这种方法，如果成功，将使广泛的他汀类药物类似物容易获得显着降低成本。

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.