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Phosphodiesterase IV inhibitor

A highly stereoselective, nickel-catalyzed P-addition of organozincates to optically pure vinylic sulfoxide (7) played a crucial role in the synthesis of the phosphodiesterase IV inhibitor L-765,527 (CDP-840) (9) (Scheme 1)." The syn-... [Pg.157]

Other drugs may also have an inhibitory effect on cytokine synthesis. Elevation of cyclic AMP has an inhibitory effect on ID2 release from lymphocytes in vitro (Didier et al., 1987) and this may be achieved by theophylline at high plasma concentrations. Selective phosphodiesterase inhibitors may also be effective and recently phosphodiesterase IV inhibitors have been demonstrated to inhibit the release of IL-4 and IL-5 from T lymphocytes in vitro (Essayan et al., 1993). [Pg.113]

Dal Piaz V, Giovannoni MP, Castellana C et al (1997) Novel heteiocyclic-fused pyridazinones as potent and selective phosphodiesterase IV inhibitors. J Med Chem 40 1417-1421... [Pg.72]

Even selective monocarbonylationof2,5-dichloropyridineinthe C-2 position could be achieved by the use of the Pd(OAc)2/dppf catalyst and by limiting the amount of the EtsN base to 1.01 equiv. to prevent overcarbonylation during the synthesis of a chloropyridine N-oxide building block of a potent phosphodiesterase IV inhibitor [81]. [Pg.313]

Choi W-B, Churchill DRH, Lynch EJ, Reider JP, Wolante PR, inventors Merck Co., Inc., assignee. Method of preparing phosphodiesterase IV inhibitors. EP 0912517 Bl. [Pg.66]

R)-(-)-baclofen 58,138 and phosphodiesterase type IV inhibitor, (R)-(—)-rolipram 59,187 were efficiently prepared with an intramolecular G-H insertion being used as a key step (Equations (49) and (50)). [Pg.187]

WARNING Renal impair is the major tox foUow administration instructions Uses CMV retinitis w/ HIV Action Selective inhibition of viral DNA synth Dose Rx 5 mg/kg IV over 1 h once/wk for 2 wk w/ probenecid Maint 5 mg/kg IV once/2 wk w/ probenecid (2 g PO 3 h prior to cidofovir, then 1 g PO at 2 h 8 h after cidofovir) X in renal impair Caution [C, -] Contra Probenecid or sulfa allergy Disp Inj SE Renal tox, chills, fever, HA, NA /D, thrombocytopenia, neutropenia Interactions t Nephrotox W/ aminoglycosides, amphot icin B, foscar-net, IV pentamidine, NSAIDs, vancomycin t effects W/zidovudine EMS Monitor ECG for hypocalcemia (t QT int val) and hypokalemia (flattened T waves) OD May cause renal failure hydration may be effective in reducing drug levels/effects Cilostazol (Pletal) TAntiplatelet, Arterial Vasodilator/ Phosphodiesterase Inhibitor] Uses Reduce Sxs of intermittent claudication Action Phosphodiesterase in inhibitor t s cAMP in pits blood vessels, vasodilation inhibit pit aggregation Dose 100 mg PO bid, 1/2 h before or 2 h after breakfast dinner Caution [C, +/-] Contra CHE, hemostatic disorders. [Pg.111]

PEE-IV Inhibitors Selective inhibitors of phosphodiesterase IV (PDE4) are in development for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Two of them contain fluorine atoms roflumilast (preregistered) bears a difluoromethyl ether and AWD-12-281 (Phase II) has a single fluorine atom (Figure 8.51). [Pg.315]

Milrinone is a phosphodiesterase type III/IV inhibitor that has vasodilatory properties and increases the force of contraction and velocity of relaxation of cardiac muscle. Milrinone has not been evaluated fully in the equine clinical setting. It produces a dose-dependent increase in heart rate, cardiac output, arterial blood pressure and ejection fraction and a reduction in right atrial, pulmonary artery pressures and systemic vascular resistance in normal anesthetized horses (Muir 1995). These changes persisted for 30 min after the termination of a constant i.v. infusion of milrinone. [Pg.210]

Chemistry conceptually similar to that described for tamoxifen analogs 218 has been applied to the synthesis of CDP840 222, a phosphodiesterase (PDE) IV inhibitor for the treatment of asthma [78]. In combination with the Liebeskind-variation of the Suzuki reaction, thiopyrimidine ether 220 was cross-coupled to pyridyl-4-boronic acid 210 to afford 221. Catalytic hydrogenation of the olefin gave rise to 222. [Pg.214]

Ducrot, P., Andrianjara, C.R. and Wrigglesworth, R. (2001) CoMFA and CoMSIA ID-quantitative structure-activity relationship model on benzodiazepine derivatives, inhibitors of phosphodiesterase. IV. 1. Comput. Aid. Mol. Des., 15, 767-785. [Pg.1028]

The principal asthma therapies have all been in clinical practice since the early 1970s and before, yet their mechanisms and potential hazards in many cases remain obscure. The trend towards inhaled corticosteroids continues to raise concerns about their long-term side-effects. This has fuelled efforts to develop safer anti-inflammatory therapies, despite the advent of fluticasone, which is 100 per cent first-pass metabolized in the liver and has fewer systemic effects (Harding, 1990). Suggestions that the long-actingy 2-agonists (salmeterol, formoterol) may be anti-inflammatory appear to be unfounded, but the possibility of an antiinflammatory effect of theophylline (Ward et al., 1993) has accelerated development of selective phosphodiesterase (PDE IV) inhibitors, which may have reduced side-effects and a better therapeutic index than theophylline itself. The immunosuppressants, such as cyclosporin A which prevents expression of IL-2 and IL-2R in T cells, are limited by toxicity to a small minority of very severe corticosteroid-dependent asthmatics. [Pg.21]

Examples of more basic, but enantioselective intramolecular carbenoid C-H insertion reactions were displayed in two very similar total syntheses of the phosphodiesterase type IV inhibitor i -(-)-rolipram (179, Scheme 44) [125, 126], In 1999, Hashimoto and coworkers utilized acceptor/acceptor diazo compound 180, with the nitrogen atom protected with a p-nitrophenyl moiety, as the carbenoid precursor. After screening a number of phthalimide-based dirhodium catalysts, Rh2(5 -BPTTL)4 (30) was found to give the optimal results, providing the cyclized product in 74% yield and 88% ee. [Pg.335]

Fig. 8.4 Yeast-based screen for inhibitors of human phosphodiesterase IV. A phosphodiesterase (PDE)-deficient yeast (PMY) will not utilize acetate as a sole carbon source and is sensitive to heat shock (55°C). Complementation with a human type IV PDE (PMY PDE) expressed from a copper-dependent (CUP1) promoter reverses the mutant phenotype. Addition of type IV PDE inhibitor (rolipram) to the complemented yeast restores the mutant phenotype (PMY -t- PDE + rolipram). Fig. 8.4 Yeast-based screen for inhibitors of human phosphodiesterase IV. A phosphodiesterase (PDE)-deficient yeast (PMY) will not utilize acetate as a sole carbon source and is sensitive to heat shock (55°C). Complementation with a human type IV PDE (PMY PDE) expressed from a copper-dependent (CUP1) promoter reverses the mutant phenotype. Addition of type IV PDE inhibitor (rolipram) to the complemented yeast restores the mutant phenotype (PMY -t- PDE + rolipram).
Aryl-l,3,4-thiadiazin-2-ones are phosphodiesterase III/IV inhibitors <1999WO9947505>. l,3,4-Thiadiazin-2-ones <1998WO9810765> are nonsteroidal contraception agents for females <1998WO9810765>. Some 1,3,4-thiadiazin-... [Pg.449]

The key step in the synthesis of CDP840 ( 108), a phosphodiesterase IV (PDE IV) inhibitor for the treatment of asthma included the Liebeskind variation of the Suzuki reaction i.e., the thiopyrimidine ether 106 was cross-coupled with pyridyl-4-boronic acid to afford 107. Catalytic hydrogenation of 107 then afforded racemic 108. [Pg.420]

Scheme 9.17 Domino reductive ring-opening/double cyclization synthesis of phosphodiesterase (PDE) IV inhibitor. Scheme 9.17 Domino reductive ring-opening/double cyclization synthesis of phosphodiesterase (PDE) IV inhibitor.
Conjugate addition of the y-butyrolactam to enals was promoted by diphenyl-prolinol trimethylsilyl ether 12 via the iminium activation process (Scheme 32, second hne) [53]. A satisfactory level of enantioselectivity was generally observed irrespective of the solvent polarity, although the use of aqueous acetonitrile was superior for optimizing the chemical yield and enantioselectivity. In addition, acidic additives had apparent effects on the reaction profile and the highest diastereoselectivity was attained with 2-fluorobenzoic acid. The synthetic utility of this site- and stereoselective transformation was demonstrated in a series of product derivatizations, including the three-step synthesis of a cAMP-specific phosphodiesterase (PDE IV) inhibitor (Scheme 32, third hne). [Pg.75]


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See also in sourсe #XX -- [ Pg.214 , Pg.241 ]




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