(R)-(-)-Rolipram - CAS 85416-75-7
Catalog number: 85416-75-7
Category: Inhibitor
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Phosphodiesterase (PDE)
(R)-(-)-Rolipram is a potent and cAMP-specific PDE4 inhibitor. It is 2.5-fold more potent than (+)-rolipram in inhibiting membrane-bound PDE 4.
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1.Zinc dependent activation of cAMP-specific phosphodiesterase (PDE4A).
Percival MD;Yeh B;Falgueyret JP Biochem Biophys Res Commun. 1997 Dec 8;241(1):175-80.
Cyclic nucleotide phosphodiesterases (PDE), including PDE4A, contain two consensus sequences (HX3HX24-26E) which have been associated with Zn2+ binding and activation with other proteins. This study shows that Zn2+ activates purified recombinant human PDE4A with an EC50 of <1 microM. The EC50 for Mg2+, the generally accepted activating metal ion, is approximately 100 microM. Zn2+ concentrations higher than 5 microM are inhibitory. Mn2+, Co2+ and Ni2+ also activate PDE4A with EC50 values of approximately 2, 3 and 10 microM, respectively. PDE4A binds 65Zn2+ with a Kd of 0.4 microM and approximately 1:1 stoichiometry. Titrations of PDE4A inhibition with Mg2+ and Zn2+ as activating metal ions showed that the competitive inhibitors R-Rolipram, CDP-840, RS-14203 and KF18280 are shifted at least 10-fold to lower potency in the presence of Zn2+. The effect is likely at the site of inhibitor binding as the Km for cAMP in the presence of Mg2+ and Zn2+ is similar (1-3 microM). The Kd of [3H]-R-Rolipram for PDE4A was increased at least 30-fold from 3 nM (with Mg2+) by the presence of Zn2+. The high affinity of Zn2+ for PDE4A indicates that this metal may play a role in the regulation of PDE4A activity.
2.SB 207499 (Ariflo), a potent and selective second-generation phosphodiesterase 4 inhibitor: in vitro anti-inflammatory actions.
Barnette MS;Christensen SB;Essayan DM;Grous M;Prabhakar U;Rush JA;Kagey-Sobotka A;Torphy TJ J Pharmacol Exp Ther. 1998 Jan;284(1):420-6.
First-generation phosphodiesterase 4 (PDE4) inhibitors, such as rolipram, inhibit the activation of immune and inflammatory cells. The clinical use of these compounds is limited by gastrointestinal side effects, such as increased acid secretion and nausea. Consequently, the challenge has been to design novel PDE4 inhibitors that maintain the anti-inflammatory actions of rolipram while achieving an improved side effect profile. Among the first of this new class of PDE4 inhibitors specifically designed to have an improved therapeutic index relative to earlier compounds is SB 207499 (Ariflo) [c-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-r-1-cyclohexanecarboxyl ic acid]. In this study, we compared the anti-inflammatory and gastric secretogogue activities of SB 207499 with those of rolipram. The cellular models used were (1) histamine release from human basophils, (2) tumor necrosis factor-alpha generation in human monocytes, (3) degranulation of human neutrophils, (4) antigen-driven proliferation and cytokine synthesis from human T cells and (5) acid secretion from isolated rabbit gastric glands. SB 207499 inhibited the activation of a variety of immune and inflammatory cells in a concentration-dependent manner: (1) histamine release in basophils [-log IC25 = 6.
3.Phosphodiesterase 4-dependent regulation of cyclic AMP levels and leukotriene B4 biosynthesis in human polymorphonuclear leukocytes.
Denis D;Riendeau D Eur J Pharmacol. 1999 Feb 19;367(2-3):343-50.
Several selective phosphodiesterase 4 inhibitors were found to be potent inhibitors of the N-formyl-Met-Leu-Phe (fMLP)-induced leukotriene B4 biosynthesis by human polymorphonuclear leukocytes with IC50s in the nanomolar range (0.09-26 nM). The rank order of potency was 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline (RS-14203) > 3-benzyl-5-phenyl-3H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (KF18280) > 8-aza-1-(3-nitrophenyl)-3-(4-pyridylmethyl)-2,4-quinazoline dione (RS-25344) > 3-cyclo-pentyloxy-N-[3,5-dichloro-4-pyridyl]-4-methoxybenzamide (RP-73401) > R-rolipram > R-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl] pyridine (CDP840)> S-rolipram. Isoproterenol (IC50 = 350 nM) and prostaglandin E2 (IC50 = 59 nM) also suppressed leukotriene B4 biosynthesis. Inhibitors of the phosphodiesterase 1 (8-methoxymethyl-1-methyl-3-(2-methylpropyl)xanthine (8-MeOMe-IBMX)), phosphodiesterase 2 (erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA)), phosphodiesterase 3 (quazinone and milrinone) and phosphodiesterase 5 (zaprinast and dipyridamole) had no inhibitory effects on the fMLP-induced leukotriene B4 biosynthesis (IC50s > 20 microM). All phosphodiesterase 4 inhibitors caused an accumulation of cellular cyclic AMP to 140-185% over the basal level of fMLP-treated control cells, comparable to that observed with high concentrations of isoproterenol and prostaglandin E2.
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CAS 85416-75-7 (R)-(-)-Rolipram

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