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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.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Gopalakrishnan R
Max Planck Institute of Psychiatry, Kraepelinstrasse 2, 80804 Munich, Germany.
Kozany C
No affiliation info available
Wang Y
No affiliation info available
Schneider S
No affiliation info available
Hoogeland B
No affiliation info available
Bracher A
No affiliation info available
Hausch F
No affiliation info available

MeSH

Crystallography, X-RayFluorescence PolarizationHumansMagnetic Resonance SpectroscopyMolecular StructurePipecolic AcidsProtein BindingSpectrometry, Mass, Electrospray IonizationStructure-Activity RelationshipSulfonamidesTacrolimusTacrolimus Binding Proteins

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 -