4C7K

11b-Hydroxysteroid Dehydrogenase Type I in complex with inhibitor

Summary for 4C7K

• Entry DOI: 10.2210/pdb4c7k/pdb
• Related: 4C7J
• Descriptor: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-ethyl-N-[(1S,3R)-5-oxidanyl-2-adamantyl]-4-[(2R)-oxolan-2-yl]-1,3-thiazole-5-carboxamide, ... (4 entities in total)
• Functional Keywords: oxidoreductase, cns penetration, structure-based design
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Endoplasmic reticulum membrane ; Single-pass type II membrane protein : P28845
• Total number of polymer chains: 4
• Total formula weight: 122696.74

Authors

Goldberg, F.W.,Dossetter, A.G.,Scott, J.S.,Robb, G.R.,Boyd, S.,Groombridge, S.D.,Kemmitt, P.D.,Sjogren, T.,Morentin Gutierrez, P.,de Schoolmeester, J.,Swales, J.G.,Turnbull, A.V.,Wild, M.J. (deposition date: 2013-09-23, release date: 2014-03-05, Last modification date: 2023-12-20)

Primary citation

Goldberg, F.W.,Dossetter, A.G.,Scott, J.S.,Robb, G.R.,Boyd, S.,Groombridge, S.D.,Kemmitt, P.D.,Sjogren, T.,Gutierrez, P.M.,Deschoolmeester, J.,Swales, J.G.,Turnbull, A.V.,Wild, M.J.
Optimization of Brain Penetrant 11Beta-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet- Induced Obese Mice.
J.Med.Chem., 57:970-, 2014

PubMed Abstract: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11β-HSD1 activity alleviates metabolic syndrome.

PubMed: 24422550
DOI: 10.1021/JM4016729

Experimental method

X-RAY DIFFRACTION (1.91 Å)