Zhao, Liqin published the artcileFK506-Binding Protein Ligands: Structure-Based Design, Synthesis, and Neurotrophic/Neuroprotective Properties of Substituted 5,5-Dimethyl-2-(4-thiazolidine)carboxylates, Computed Properties of 101-98-4, the publication is Journal of Medicinal Chemistry (2006), 49(14), 4059-4071, database is CAplus and MEDLINE.
Structure-based design and discovery of novel neuroimmunophilin FK506-binding protein (FKBP) ligands were pursued in the present study. The binding mode of the known FKBP ligand, 3-(3-pyridyl)-1-propyl- (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, in a complex with FKBP12 was investigated using LUDI simulation and upon which a novel scaffold structure predicted to possess improved binding affinity was designed. A virtual combinatorial library composed of diverse combinations of two substituted groups was constructed using Project Library, followed by an automated screening of the library against the ligand binding site on FKBP52 using DOCK. Forty-three candidate compounds I [R1 = Me3C, EtCMe2, cyclopentyl, cyclohexyl, n-hexyl, n-octyl, Ph, 4-ClC6H4, 2,4,6-Me3C6H2, PhCMe2CH2; R2 = 3-(3-pyridyl)-1-Pr, Ph(CH2)3, H2C:CH(CH2)8, etc.] that displayed favorable binding with the receptor were identified and synthesized. The neurotrophic activity of the candidate compounds was evaluated on chick dorsal root ganglion cultures in vitro. As a result, 15 compounds exhibited pos. effects on ganglion neurite outgrowth in the presence of 0.15 ng/mL NGF, among which 7 compounds at testing concentrations of 1 pM and 100 pM showed greater efficacy than 1 at 100 pM. I [R1 = Me3C; R2 = 3-(3-pyridyl)-1-propyl; (II)] afforded the most potent effect in promoting the processes of neurite outgrowth and which was in a concentration-dependent manner from 1 pM to 100 pM. Half-maximal effect occurred at about 10 pM. Moreover, II at a dosage of 10 mg/kg was found to be significantly neuroprotective in a mouse peripheral sympathetic nerve injury model induced by 8 mg/kg 6-hydroxydopamine. This study further suggests the clin. potential of novel FKBP ligands as a new therapeutic approach in the treatment of neurodegenerative disorders, such as Parkinson’s disease.
Journal of Medicinal Chemistry published new progress about 101-98-4. 101-98-4 belongs to alcohols-buliding-blocks, auxiliary class Amine,Benzene,Alcohol, name is 2-(Benzyl(methyl)amino)ethanol, and the molecular formula is C9H11BO4, Computed Properties of 101-98-4.
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