FKBPs Structure-Based Design, Sythesis And Screening Of Compounds With Promoting Nerves Growth Activity

Neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease etc., mainly appear in aged people and are difficult to treat. With increasing of people's life span, neurodegenerative diseases' incidence rate is increasing accordingly. And these diseases have been a critical threat against human's health. Neurotrophic factors(NTFs), as a kind of active endogenetic nerve proteins, have the activity of promoting nerves growth.. However, clinical application of proteins is severely limited by their low bioavailability and inability to across the blood-brain barrier. Thus, to find effective small molecule with promoting nerves growth activity to overcome above defects is a study direction of treatment of neurodegenerative disease.FK506, a immunosuppresant, has been found able to promote damaged nerves regrovvth. It seems that FK506 binding proteins (FKBPs) would be a novel target of neurodegenerative diseases. On the basis of GPI-1046(a ligand of FKBP12) in complex with FKBP12, a set of 2,2-dimethyl-N-alkyl dioxo-4-thiazolidine carboxylate derivatives was designed, and computer-aided screened by DOCK4.0 based on the structure of FKBP52. 22 of 500 highest score compounds had been synthesized and their neurotrophic actions had been examined. According to the results of activity evaluation and principle of bioisosterism, 11 compounds of 2,2-dimethyl-N-alkyldioxo-4-oxazolidine carboxylate dei'.vatives and 18 compounds of 2,2-dimethyl-N-alkyl benzenesulfonyl- 4-oxazolidine carboxylate derivatives, were designed and synthesized. Their activitieswere examined on chick dorsal root ganglion cultures (DRGs). Synthesis of three sets of compounds has been studied, and synthesis route of N-sulfonyl-4-oxazolidine carboxylate derivatives was improved.51 of three sets of compounds were synthesized. According to the results of activity evaluation, 18 of 41 second screened compounds showed more potential than GPI-1046 in DRGs at different doses. Among them, 11 compounds showed more potential than GPI-1046 in DRGs at both IpM and l00pM, possesing certain outlook to develop, their dosage dependent manner is studying. The other 10 compounds have been first screened, and 5 of them showed significant activity of promoting nerve growth. Their second screening is doing.