4P38
Human 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with AZD8329
Summary for 4P38
| Entry DOI | 10.2210/pdb4p38/pdb |
| Related | 4HFR |
| Descriptor | Corticosteroid 11-beta-dehydrogenase isozyme 1, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid, ... (5 entities in total) |
| Functional Keywords | alpha beta, rossmann fold, nadp, 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 | 2 |
| Total formula weight | 60838.64 |
| Authors | Ogg, D.,Hargreaves, D.,Gerhardt, S. (deposition date: 2014-03-06, release date: 2014-04-30, Last modification date: 2024-02-28) |
| Primary citation | Scott, J.S.,deSchoolmeester, J.,Kilgour, E.,Mayers, R.M.,Packer, M.J.,Hargreaves, D.,Gerhardt, S.,Ogg, D.J.,Rees, A.,Selmi, N.,Stocker, A.,Swales, J.G.,Whittamore, P.R. Novel acidic 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329). J.Med.Chem., 55:10136-10147, 2012 Cited by PubMed Abstract: Inhibition of 11β-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability. PubMed: 23088558DOI: 10.1021/jm301252n PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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