4W1O

PDE4D complexed with inhibitor

4W1O の概要

• エントリーDOI: 10.2210/pdb4w1o/pdb
• 分子名称: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, N-(3,5-dichloropyridin-4-yl)-3-[(3-ethyl-1,2-oxazol-5-yl)methoxy]-4-methoxybenzamide, ZINC ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, pde4d, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 167338.79

構造登録者

Sorensen, M.D. (登録日: 2014-08-14, 公開日: 2014-11-05, 最終更新日: 2024-05-08)

主引用文献

Felding, J.,Sorensen, M.D.,Poulsen, T.D.,Larsen, J.,Andersson, C.,Refer, P.,Engell, K.,Ladgefoged, L.G.,Thormann, T.,Vinggaard, A.M.,Hegardt, P.,Sohoel, A.,Nielse, S.F.
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
J.Med.Chem, 57:5893-5903, 2014

PubMed Abstract: 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.

PubMed: 24984230
DOI: 10.1021/jm500378a

実験手法

X-RAY DIFFRACTION (2.2 Å)