Substituted alpha-Hydroxy Acids and Their Thioesters as Pharmacophores: Development of New Peptide Derived Caspase Inhibitors

半胱天冬酶调节对高等生物体至关重要的细胞过程，例如促进炎症或介导凋亡。虽然在正常条件下发挥重要的稳态功能，但炎症和细胞凋亡的失调可能导致致命的后果。因此，半胱天冬酶介导的信号传导途径的药理学调节或破坏代表了一个有前途的治疗靶点，原则上，可以通过使用小分子抑制剂来实现。半胱天冬酶的肽类抑制剂有两个组成部分：负责抑制酶的相关药效团部分，和活性位点附近的额外的相互作用所需的肽元素，我们推断，有效的药效团部分与“变形”肽段的组合可能是合成生物可利用的强抑制剂的关键。我们选择高度取代的α-羟基-β-氨基酸和它们的硫酯作为一般的药效学部分，羟基取代基单元作为“变形”肽段。不对称羟醛缩合反应的最新进展使半合理的组合方法成为可能。

Caspases regulate cellular processes of fundamental importance to higher organisms, e.g. the promotion of inflammation of the mediation of apoptosis. While serving important homeostatic functions under normal conditions, the deregulation of inflammation and apoptosis can lead to fatal consequences. Therefore, pharmacological regulation or disruption of caspase mediated signalling pathways represents a promising therapeutic target which, in principle, can be achieved by using small molecule inhibitors. Peptidylic inhibitors of caspases have two components: the relevant pharmacophore moiety responsible for the inhibition of the enzyme, and a peptide element required for additional interactions near the active site.We reasoned that a combination of effective pharmacophore moieties with "morphed" peptide segments may be the key to synthesis of bioavailable strong inhibitors. We chose highly substituted a-hydroxy-ß-amino acids and their thioesters as general pharmacophoric moities and hydroxyethylene units as the "morphed" peptide segments. Semirational, combinatorial approach leading to the potential inhibitors should be possible by recent developments in asymmetric aldol reactions.