Discovery and Early Clinical Development of 2-{6-[2-(3,5-Dichloro-4-pyridyl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (LEO 29102), a Soft-Drug Inhibitor of Phosphodiesterase 4 for Topical Treatment of Atopic Dermatitis
| Autor: | Jakob Felding, Morten Dahl Sørensen, Karen Margrethe Engell, Pontus Hegardt, Jens Christian Højland Larsen, Anne Marie Vinggaard, Anders Søhoel, Pia Refer, Simon Feldbaek Nielsen, Christina Andersson, Lotte G. Ladefoged, Tina Dahlerup Poulsen, Thorsten Thormann |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Drug Pyridines media_common.quotation_subject Pharmacology Crystallography X-Ray Dermatitis Atopic Structure-Activity Relationship chemistry.chemical_compound Phosphodiesterase-4 Acetamides Drug Discovery medicine Humans Structure–activity relationship Roflumilast media_common Dose-Response Relationship Drug Molecular Structure Drug discovery Atopic dermatitis medicine.disease Cyclic Nucleotide Phosphodiesterases Type 4 chemistry Drug delivery Molecular Medicine Phosphodiesterase 4 Inhibitors Piclamilast medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 57:5893-5903 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm500378a |
| Popis: | Development of orally available phosphodiesterase 4 (PDE4) inhibitors as anti-inflammatory drugs has been going on for decades. However, only roflumilast has received FDA approval. One key challenge has been the low therapeutic window observed in the clinic for PDE4 inhibitors, primarily due to PDE4 mediated side effects. Here we describe our approach to circumvent this issue by applying a soft-drug concept in the design of a topically acting PDE4 inhibitor for treatment of dermatological diseases. We used a fast follower approach, starting from piclamilast. In particular, simultaneous introduction of 2'-alkoxy substituents and changing an amide to a keto linker proved to be beneficial when designing potential soft-drug candidates. This effort culminated in identification of LEO 29102 (20), a potent, selective, and soft-drug PDE4 inhibitor with properties suitable for patient-friendly formulations giving efficient drug delivery to the skin. Compound 20 has reached phase 2 and demonstrated clinically relevant efficacy in the treatment of atopic dermatitis. |
| Databáze: | OpenAIRE |
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