4BB5

Free-Wilson and Structural Approaches to Co-optimising Human and Rodent Isoform Potency for 11b-Hydroxysteroid Dehydrogenase Type 1 11b-HSD1 Inhibitors

Summary for 4BB5

• Entry DOI: 10.2210/pdb4bb5/pdb
• Related: 1XU7 1XU9 2BEL 4BB6
• Descriptor: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4-cyclopentyl-N-[(1S,3R)-5-oxidanyl-2-adamantyl]-2-[[(3S)-oxolan-3-yl]amino]pyrimidine-5-carboxamide, ... (4 entities in total)
• Functional Keywords: oxidoreductase
• 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: 134403.10

Authors

Goldberg, F.W.,Leach, A.G.,Scott, J.S.,Snelson, W.L.,Groombridge, S.D.,Donald, C.S.,Bennett, S.N.L.,Bodin, C.,Morentin Gutierrez, P.,Gyte, A.C. (deposition date: 2012-09-20, release date: 2012-11-28, Last modification date: 2024-05-08)

Primary citation

Goldberg, F.W.,Leach, A.G.,Scott, J.S.,Snelson, W.L.,Groombridge, S.D.,Donald, C.S.,Bennett, S.N.L.,Bodin, C.,Morentin Gutierrez, P.,Gyte, A.C.
Free-Wilson and Structural Approaches to Co-Optimising Human and Rodent Isoform Potency for 11Beta-Hydroxysteroid Dehydrogenase Type 1 (11Beta-Hsd1) Inhibitors
J.Med.Chem., 55:10652-, 2012

PubMed Abstract: 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) has been a target of intensive research efforts across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome. To demonstrate the value of 11β-HSD1 in preclinical models, we required inhibitors with good potency against both human and rodent isoforms. Herein, we describe our efforts to understand how to co-optimize human and murine potency within the (5-hydroxy-2-adamantyl)-pyrimidine-5-carboxamide series. Two approaches are described-a data-driven (Free-Wilson) analysis and a structure-based design approach. The conclusions from these approaches were used to inform an efficient campaign to design compounds with consistently good human/murine potency within a logD(7.4) range of 1-3. Compounds 20 and 26 demonstrated good rodent PK, which allowed us to demonstrate a PK/PD relationship in rat and mouse. We then evaluated 26 against glycemic and body weight end points in murine disease models, where it demonstrated glucose and body weight efficacy at 300 mg/kg/day but only body weight efficacy at 50 mg/kg/day, despite providing >90% target engagement in the liver.

PubMed: 23153367
DOI: 10.1021/JM3013163

Experimental method

X-RAY DIFFRACTION (2.2 Å)