Drug Discovery Based On The Structure Of FKBPs: Design, Synthesis And Evaluation Of 2,2-Dimethyl-[1,3]-dioxolane-4-dicarboxylic Acid Derivatives As Neuroimmunophilin Ligands

Neurodegenerative disease, including Parkinson's disease, Alzheimer's disease, Huntington's disease, etc., mainly appear in aged people. At currently there are no effective strategies in the treatment of this disease. Along with the growing population aging, the incidence of neurodegenerative disease is increasing accordingly. It seriously threatens human's health. Neurotrophic factors (NTFs), as a kind of active endogenetic nerve proteins, have the neural activity. However, their clinical development is hindered by their low bioavailability and inability across the blood-brain-barrier. Thus, to find effective small molecules with promoting nerves growth activity to overcome above defects is a study direction of treatment of neurodegenerative disease.FK506, an immunosuppressant, has been found to be able to promote damaged nerve regeneration. It seems that FK506-binding proteins (FKBPs) would become a novel target of neurodegenerative disease. Using GPI-1046 (a ligand of FKBP12) as a template, based on the structure-activity relationship of FKBP12 ligands and the structure of FKBP52-domain 1, a set of 2,2-dimethyl-[l,3]-dioxolane-4-dicarboxylic acid derivatives was designed. A model of chick embryos dorsal root ganglion (DRG) cultures free of serum and a model of NG108-15 cell injured by H₂O₂ were applied to evaluate neurotrophic activity of the new compounds.27 target compounds were designed and synthesized. In cultured chick DRGs, 14 compounds exhibited more activity to promote neurite outgrowth in vitro than that of GPI-1046 at the concentration of 1 or 100 pmol/L. 7 compounds produced more activity than that of GPI-1046 at both doses. 2 compounds showed a significantly protective effect in the model of H₂O₂-induced NG108-15 cell damage.Compared the result of biological screening and the 3D-QSAR model derived by using CoMFA method, the SAR of these compounds is revealed: 1) Substituent R² has more effect on the activity of compounds than that of substituent R¹ and Z. 2) When R² is an alkyl group, the activity of compounds is more active than that of phenyl and heterocycle group. Moreover, it is suitable that the bond-chain of R² is comprised of 2-6 atoms. The bond-chain may contain sulphur, hydroxy or ester groups. 3) The critical fragments containing acylamino group exhibited more active than that of easter groups. However, all of the fragments possessed easter group also contained phenyl or heterocycle groups. While most of the good compounds constituted with small motifs (less than 4 atoms), the effect of ester groups is to be solved by further experiments.