Piclamilast - CAS 144035-83-6
Category: Inhibitor
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Molecular Weight:
Phosphodiesterase (PDE)
Piclamilast is a potent and selective phosphodiesterase-4 (PDE4) inhibitor (IC50 = 1 nM at PDE4 from human neutrophils) with >19,000-fold selectivity over other PDE isoenzymes.
≥99% by HPLC
Piclamilast; RP-73401; RP 73-401; RP 73401; RP 73 401; RP73401; RP 73401; 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridinyl)-4-methoxybenzamide; N-(3,5-Dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide
Store in a cool and dry place (or refer to the Certificate of Analysis).
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1.Effects of phosphodiesterase inhibitors on tension induced by norepinephrine and accumulation of cyclic nucleotides in isolated human prostatic tissue.
Uckert S;Sormes M;Kedia G;Scheller F;Knapp WH;Jonas U;Stief CG Urology. 2008 Mar;71(3):526-30. doi: 10.1016/j.urology.2007.10.051.
OBJECTIVES: ;To further evaluate the mechanism of action of phosphodiesterase (PDE) inhibitors on the human prostate, the effects of PDE4 and PDE5 inhibitors on the tension induced by norepinephrine (NE) and on the intracellular levels of cyclic nucleotides in isolated human prostatic tissue were investigated.;METHODS: ;Using the organ bath technique, the effects of increasing concentrations (1 nM to 10 microM) of the PDE5 inhibitors sildenafil, tadalafil, and vardenafil and the PDE4 inhibitors rolipram and RP 73401 on the tension induced by NE (40 microM) of prostate strip preparations were investigated. The accumulation of cyclic guanosine monophosphate and cyclic adenosine monophosphate in response to drug exposure was determined by radioimmunoassays.;RESULTS: ;The tension induced by NE was dose dependently reversed by the drugs with the following rank order of efficacy: tadalafil greater than RP 73401 greater than rolipram greater than or equal to vardenafil greater than sildenafil. The maximal reversion of tension values ranged from 52.3% (tadalafil) to 17% (sildenafil). Of the PDE inhibitors, only tadalafil induced a 50% reversion of the initial tension. The most prominent enhancement in tissue cyclic adenosine monophosphate was registered in response to RP 73401 (11-fold), and cyclic guanosine monophosphate levels were significantly elevated by tadalafil, vardenafil, and sildenafil (28-fold, 12-fold, and 3-fold, respectively).
2.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;Sørensen MD;Poulsen TD;Larsen J;Andersson C;Refer P;Engell K;Ladefoged LG;Thormann T;Vinggaard AM;Hegardt P;Søhoel A;Nielsen SF J Med Chem. 2014 Jul 24;57(14):5893-903. doi: 10.1021/jm500378a. Epub 2014 Jul 1.
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.
3.Inhibitor binding to type 4 phosphodiesterase (PDE4) assessed using [3H]piclamilast and [3H]rolipram.
Zhao Y;Zhang HT;O'Donnell JM J Pharmacol Exp Ther. 2003 May;305(2):565-72.
Piclamilast is a type 4 phosphodiesterase (PDE4) inhibitor with equal affinity for the high-affinity rolipram binding site (HARBS) and low-affinity rolipram binding site (LARBS). The binding of [(3)H]piclamilast to preparations of rat brain and peripheral tissue was investigated and compared with that of [(3)H]rolipram. [(3)H]piclamilast binding was high-affinity, saturable, reversible, and partially Mg(2+)-dependent. Binding was detected both to membrane and soluble fractions, with K(d) values of 3.1 and 4.5 nM, respectively. The B(max) values for [(3)H]piclamilast were about 1.5-fold greater than that of [(3)H]rolipram binding, suggesting that [(3)H]piclamilast, but not [(3)H]rolipram, binds to LARBS as well as the HARBS. The HARBS was present in all the brain regions examined, but not in peripheral tissues. All PDE4 inhibitors tested were potent competitors for [(3)H]piclamilast binding; the competition curves for rolipram, desmethylpiclamilast, ICI 63,197, and Ro 20-1724 were better described by a two-site model, while the competition curves for piclamilast, cilomilast, roflumilast, and CDP 840 were adequately described by a one-site model. Inhibitors of other PDE families were much less potent.
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CAS 144035-83-6 Piclamilast

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