NuclearReceptors2018 Poster Presentations (1) (7 abstracts)
Next generation glucocorticoid receptor modulators
Karl Edman 1, , Graham Belfield 1 , Matthew Dearman 1 , Goran Edenro 1 , Stefan Geschwindner 2 , Tove Hegelund-Myrbäck 1 , Martin Hemmerling 1 , Ramon Hendrickx 1 , Christina Keen 1 , Carina Kärrman-Mårdh 1 , Matti Lepistö 1 , Suman Mitra 1 , Susan Monkley 1 , Susanne Prothon 1 , Lena Ripa 1 , John Steele 1 , Outi Vaarala 1 , Lisa Wissler 2 & Lisa Öberg 1
1Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 43183, SE, Sweden; 2Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
Synthetic glucocorticoids bind to the glucocorticoid receptor (GR) and have been used for nearly 70 years to treat inflammatory diseases. However, their use is limited by adverse effects such as diabetes, muscle wasting and osteoporosis. High throughput screening identified a novel non-steroidal scaffold with great potential for chemical optimization. Through rational design we developed the indazole ether series which combines high potency with structural motifs that provide vectors to key functional areas of the receptor. Exploitation of novel pockets within receptor enabled us to generate AZD7594, a GR agonist with properties optimized for inhaled administration with high potency, long lung retention and minimal systemic exposure. AZD7594 is currently in a phase II trial for asthma.
To identify an oral agent, we modified the screening strategy to search compounds with good bioavailablility and with different mechanistic properties. Again, we started from the indazole ether series and used rational design to generate partial agonists with potential for differentiation. Evaluation in both human in vitro systems and in rat in vivo models led to the discovery of AZD9567, a compound that exhibited full inhibition of TNFα release in human whole blood after LPS stimulation but with no induction of gluconeogenic enzymes in primary hepatocytes. AZD9567 is currently evaluated vs the effects of prednisolone in clinical studies in healthy volunteers.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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