4w1o | pdb_00004w1o
PDE4D complexed with inhibitor
Structural highlights
Disease[PDE4D_HUMAN] Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. Defects in PDE4D are the cause of acrodysostosis type 2, with or without hormone resistance (ACRDYS2) [MIM:614613]. ACRDYS2 is a pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems.[1] Function[PDE4D_HUMAN] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.[2] [3] Publication Abstract from PubMedDevelopment 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. 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.,Felding J, Sorensen MD, Poulsen TD, Larsen J, Andersson C, Refer P, Engell K, Ladefoged LG, Thormann T, Vinggaard AM, Hegardt P, Sohoel A, Nielsen SF J Med Chem. 2014 Jul 24;57(14):5893-903. doi: 10.1021/jm500378a. Epub 2014 Jul 1. PMID:24984230[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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