Cyclopropanecarboxylic acid, 1-[5-(1,3-dihydro-1-oxo-5-isobenzofuranyl)-8-methoxy[1,2,4]triazolo[1,5-a]pyridin-2-yl]-, 2-methylpropyl ester

Biological Activity

LEO 39652 is a dual-soft PDE4 inhibitor with IC50s of 1.2 nM, 1.2 nM, 3.0 nM and 3.8 nM for PDE4A, PDE4B, PDE4C and PDE4D, respectively. LEO 39652 also inhibits TNF-α with an IC50 value of 6.0 nM. LEO 39652 is used for topical research of Atopic dermatitis (AD) [1]. LEO 39652 shows unbound in vitro potency when measured as LPS induced TNF-α release in human peripheral blood mononuclear cells (PBMC), incubated in serum free medium. LEO 39652 shows a relatively high binding to human serum albumin[2]. LEO 39652 is inactivated both in blood and liver (dual-soft) while stabled in the skin[1].Pharmacokinetic AnalysisLEO 39652 exhibits total clearance (rats 930, minipigs 200 and monkey 300 mL/min/kg) and ratio to total AUC (rats 4, minipigs 6 and monkey 6 %) following intravenous administration (rats 0.075, minipigs 0.5 and monkeys 2.0 mg/kg)[1].

References

[1]. Jens Larsen, et al. Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3 H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis. J Med Chem. 2020 Dec 10;63(23):14502-14521. [2]. Stefan Eirefelt, et al. Evaluating Dermal Pharmacokinetics and Pharmacodymanic Effect of Soft Topical PDE4 Inhibitors: Open Flow Microperfusion and Skin Biopsies. Pharm Res. 2020 Nov 13;37(12):243.