molecules of the month

LEO 134310 is a non-steroidal, selective glucocorticoid receptor (GR) agonist in Ph. I for plaque psoriasis. Glucocorticoid receptor modulators are widely used in tissue-restricted forms (think Flonase) for their acute effects, but prolonged engagement of GR is undesirable. Previously LEO Pharma described the identification of this topical clinical candidate through a dual-soft drug strategy (rapid metabolism in both blood and liver) to limit systemic exposure and shorten skin residence time. The campaign started with a previously disclosed inhaled GR agonist (AZD7594), but the N1-aryl-indazole needed to be replaced for skin use due to strong UV absorbance. Amides were successfully used as isosteres of the indazole (which is interesting as normally chemists try to go in the opposite direction for metabolic…