4HX5

Crystal structure of 11 beta-HSD1 in complex with SAR184841

Summary for 4HX5

• Entry DOI: 10.2210/pdb4hx5/pdb
• Descriptor: Corticosteroid 11-beta-dehydrogenase isozyme 1, 4-[5-(4-tert-butylpiperazin-1-yl)pyridin-2-yl]-N-[(1R,2S,3S,5S,7s)-5-carbamoyltricyclo[3.3.1.1~3,7~]dec-2-yl]-3,4-dihydroquinoxaline-1(2H)-carboxamide, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total)
• Functional Keywords: 11beta, hydroxysteroid, dehydrogenase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 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: 132616.21

Authors

Loenze, P.,Schimanski-Breves, S.,Engel, C.K. (deposition date: 2012-11-09, release date: 2013-05-08, Last modification date: 2023-09-20)

Primary citation

Venier, O.,Pascal, C.,Braun, A.,Namane, C.,Mougenot, P.,Crespin, O.,Pacquet, F.,Mougenot, C.,Monseau, C.,Onofri, B.,Dadji-Faihun, R.,Leger, C.,Ben-Hassine, M.,Van-Pham, T.,Ragot, J.L.,Philippo, C.,Farjot, G.,Noah, L.,Maniani, K.,Boutarfa, A.,Nicolai, E.,Guillot, E.,Pruniaux, M.P.,Gussregen, S.,Engel, C.,Coutant, A.L.,de Miguel, B.,Castro, A.
Discovery of SAR184841, a potent and long-lasting inhibitor of 11beta-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D
Bioorg.Med.Chem.Lett., 23:2414-2421, 2013

PubMed Abstract: Starting from 11β-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11β-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.

PubMed: 23478147
DOI: 10.1016/j.bmcl.2013.02.018

Experimental method

X-RAY DIFFRACTION (2.19 Å)