FKBP12-binding domain analogues of FK506 are potent, nonimmunosuppressive neurotrophic agents in vitro and promote recovery in a mouse model of parkinson's disease

• Published in: Bioorganic & medicinal chemistry letters Vol. 7; no. 13; pp. 1785 - 1790
• Main Authors: Hamilton, G.S., Huang, W., Connolly, M.A., Ross, D.T., Guo, H., Valentine, H.L., Suzdak, P.D., Steiner, J.P.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 08.07.1997; Elsevier
• Subjects: Biological and medical sciences; Catecholaminergic system; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Nitrogen heterocycle; Rodentia; Parkinson disease; Neuroprotective agent; Antiparkinson agent; In vitro; Dose activity relation; Ester; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Structure activity relation; Mouse; Animal; Six membered ring; Central nervous system disease; Piperidine derivatives; Carboxamide; Degenerative disease; Brain (vertebrata)
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(97)00304-1

A series of simple N-(glyoxyl)pipecolate esters were synthesized as mimics of the FKBP12- binding domain portion of FK506. Compounds which were effective inhibitors of the prolyl isomerase activity of FKBP12 were extraordinarily potent neurotrophic agents in vitro, and were effective in a mouse model of Parkinson's Disease. These results suggest that FKBP12 ligands have therapeutic utility in neurodegenerative diseases. A series of simple N-(glyoxyl)pipecolate esters were synthesized as mimics of the FKBP12- binding domain portion of FK506. Compounds which were effective inhibitors of the prolyl isomerase activity of FKBP12 were extraordinarily potent neurotrophic agents in vitro, and were effective in a mouse model of Parkinson's Disease. These results suggest that FKBP12 ligands have therapeutic utility in neurodegenerative diseases.