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

被引：60

作者：

Felding, Jakob ^{[1
]}

Sorensen, Morten D. ^{[1
]}

Poulsen, Tina D. ^{[1
]}

Larsen, Jens ^{[1
]}

Andersson, Christina ^{[1
]}

Refer, Pia ^{[1
]}

Engell, Karen ^{[1
]}

Ladefoged, Lotte G. ^{[1
]}

Thormann, Thorsten ^{[1
]}

Vinggaard, Anne Marie ^{[1
]}

Hegardt, Pontus ^{[1
]}

Sohoel, Anders ^{[1
]}

Nielsen, Simon Feldbaek ^{[1
]}

机构：

[1] LEO Pharma AS, New Prod Discovery & Global Dev, DK-2750 Ballerup, Denmark

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 14期

关键词：

D O I：

10.1021/jm500378a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 dinic 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.

引用

页码：5893 / 5903

页数：11

共 13 条

[11] Malignancy concerns of topical calcineurin inhibitors for atopic dermatitis: facts and controversies [J].

Thaci, Diamant ;

Salgo, Rebekka .

CLINICS IN DERMATOLOGY, 2010, 28 (01) :52-56

[12]

WATSON W, 2011, J ALLERGY CLIN IM S1, V7, pS4

[13] The Atopic March: Progression from Atopic Dermatitis to Allergic Rhinitis and Asthma [J].

Zheng, Tao ;

Yu, Jinho ;

Oh, Min Hee ;

Zhu, Zhou .

ALLERGY ASTHMA & IMMUNOLOGY RESEARCH, 2011, 3 (02) :67-73

← 1 2 →