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Exploration of pipecolate sulfonamides as binders of the FK506-binding proteins 51 and 52.
J Med Chem. 2012 May 10; 55(9):4123-31.JM

Abstract

FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products, which tightly bind to most FKBP family members, including FKBP51 and FKBP52. A bioisosteric replacement of the α-ketoamide moiety of rapamycin and FK506 with a sulfonamide was envisaged with the retention of the conserved hydrogen bonds. A focused solid support-based synthesis protocol was developed, which led to ligands with submicromolar affinity for FKBP51 and FKBP52. The molecular binding mode for one sulfonamide analogue was confirmed by X-ray crystallography.

Authors+Show Affiliations

Max Planck Institute of Psychiatry, Kraepelinstrasse 2, 80804 Munich, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22455398

Citation

Gopalakrishnan, Ranganath, et al. "Exploration of Pipecolate Sulfonamides as Binders of the FK506-binding Proteins 51 and 52." Journal of Medicinal Chemistry, vol. 55, no. 9, 2012, pp. 4123-31.
Gopalakrishnan R, Kozany C, Wang Y, et al. Exploration of pipecolate sulfonamides as binders of the FK506-binding proteins 51 and 52. J Med Chem. 2012;55(9):4123-31.
Gopalakrishnan, R., Kozany, C., Wang, Y., Schneider, S., Hoogeland, B., Bracher, A., & Hausch, F. (2012). Exploration of pipecolate sulfonamides as binders of the FK506-binding proteins 51 and 52. Journal of Medicinal Chemistry, 55(9), 4123-31. https://doi.org/10.1021/jm201747c
Gopalakrishnan R, et al. Exploration of Pipecolate Sulfonamides as Binders of the FK506-binding Proteins 51 and 52. J Med Chem. 2012 May 10;55(9):4123-31. PubMed PMID: 22455398.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exploration of pipecolate sulfonamides as binders of the FK506-binding proteins 51 and 52. AU - Gopalakrishnan,Ranganath, AU - Kozany,Christian, AU - Wang,Yansong, AU - Schneider,Sabine, AU - Hoogeland,Bastiaan, AU - Bracher,Andreas, AU - Hausch,Felix, Y1 - 2012/04/19/ PY - 2012/3/30/entrez PY - 2012/3/30/pubmed PY - 2012/9/13/medline SP - 4123 EP - 31 JF - Journal of medicinal chemistry JO - J Med Chem VL - 55 IS - 9 N2 - FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products, which tightly bind to most FKBP family members, including FKBP51 and FKBP52. A bioisosteric replacement of the α-ketoamide moiety of rapamycin and FK506 with a sulfonamide was envisaged with the retention of the conserved hydrogen bonds. A focused solid support-based synthesis protocol was developed, which led to ligands with submicromolar affinity for FKBP51 and FKBP52. The molecular binding mode for one sulfonamide analogue was confirmed by X-ray crystallography. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/22455398/Exploration_of_pipecolate_sulfonamides_as_binders_of_the_FK506_binding_proteins_51_and_52_ DB - PRIME DP - Unbound Medicine ER -