Discovery of L-791,943: A potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor

Guay, Daniel; Hamel, P.; Blouin, Marc; Brideau, Christine; Chan, Chi Chung; Chauret, Nathalie; Ducharme, Yves; Huang, Zheng; Girard, M. Fusco; Jones, Tom R.; Masson, P.; McAuliffe, Malia; Piechuta, H.; Silva, José; Young, Robert N.; Girard, Yves

doi:10.1016/s0960-894x(02)00190-7

Cited by 51 publications

(24 citation statements)

References 19 publications

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“…However, severe limiting side effects precluded the development of the first generation inhibitors such as (R)-rolipram (37) and its analogues (Table 6). From Rolipram, CDP-840 (38) was developed as the lead structure of the second generation of PDE inhibitors. Despite being a potent PDE4 inhibitor (GST-PDE4A IC 50 = 0.43 nM, HWB (TNF-α) IC 50 = 16 nM), this compound suffered from extensive metabolism in vitro with a consequent short halflife in vivo.…”

Section: Cyclic Nucleotide Phosphodiesterases Inhibitorsmentioning

confidence: 99%

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Polyfluorinated Groups in Medicinal Chemistry

2015

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Introduction of novel and diverse functional groups in drug discovery is always seen with hesitancy until good activity and low toxicity characteristics are proven. The introduction of fluorine in drug-like compounds is now a well-accepted strategy in medicinal chemistry. However, polyfluoroalkyl groups, with the exception of trifluoromethyl substituents, are not well explored yet. Our aim is to show to the readers how polyfluorinated groups can be beneficial to the properties of pharmaceutically active compounds by highlighting the structure-activity relationship (SAR) studies that led to the selection of polyfluorinated moieties as key structural features. Despite the fact that the use of higher polyfluoroalkyl/aryl moieties is still in its infancy, we believe that they will soon acquire the same importance of their lower parents.

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Section: Cyclic Nucleotide Phosphodiesterases Inhibitorsmentioning

confidence: 99%

“…Moreover, the potential for causing emesis, one of the major drawbacks of typical PDE4 inhibitors, was also assessed. Ferrets could be dosed orally with up to 30 mg/kg of L-791943 (50), with plasma concentrations reaching 14 mM without causing emesis [38].…”

Section: Cyclic Nucleotide Phosphodiesterases Inhibitorsmentioning

confidence: 99%

Polyfluorinated Groups in Medicinal Chemistry

2015

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“…Increased public awareness in this field will undoubtedly promote the identification of new compounds that might be effective in the treatment of this sexual disorder [62,63,64]. Due to the unending charge to conceive a first-line treatment more advanced than the previous options and with superior efficacy and safety, research efforts will continue to offer a promising future for the therapy of ED.…”

Section: Resultsmentioning

confidence: 99%

Strategies in the oral pharmacotherapy of male erectile dysfunction viewed from bench and bedside (Part II)

Stief¹,

Ückert²,

Jonas³

2005

The Journal of Men's Health & Gender

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Abbreviations ED, erectile dysfunction sGC, guanylyl cyclase cGMP, cyclic guanosine monophosphate NO, nitric oxide EFS, electrical field stimulation PDE, phosphodiesterase a-MSH, melanocyte-stimulating hormone ACTH, adrenocorticotropin (adrenocorticotropic hormone) MC-R, melanocortin receptors GH, growth hormone LH, luteinizing hormone FSH, follicle-stimulating hormone IGF-1, insulin-like growth factor NOS, nitric oxide synthase rGH, recombinant GH ß 2005 WPMH GmbH. Published by Elsevier Ireland Ltd.

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“…Current pharmaceutical applications aim at providing enhanced metabolic stability in drug candidates, which frequently carry the 1,1,1,3,3,3‐hexafluoropropan‐2‐ol motif, as demonstrated by the vitamin D 3 analogues falecalcitriol5 and RO0652299,6 the malonyl‐CoA decarboxylase inhibitors,7 the PDE4 inhibitor L ‐791,943,8 the LXR agonist T0901317,9 and the platelet aggregation inhibitor RO0211421 10.…”

Section: Introductionmentioning

confidence: 99%

Regioselective Friedel−Crafts Alkylation of Anilines and Amino‐Substituted Heteroarenes with Hexafluoroacetone Sesquihydrate

2003

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A variety of arenes, including anilines, pyrroles, indoles, aminooxazoles, aminothiazoles, aminoquinolines, and aminopyridines, underwent regioselective Friedel−Crafts alkylation in neat hexafluoroacetone sesquihydrate in a broad range of temperatures, reaction times, and yields (2%−94%) depending strongly on the electron density of the substrate. Prior N,N-dibenzylation of aniline and 2-aminopyridine

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Discovery of L-791,943: A potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor

Cited by 51 publications

References 19 publications

Polyfluorinated Groups in Medicinal Chemistry

Polyfluorinated Groups in Medicinal Chemistry

Strategies in the oral pharmacotherapy of male erectile dysfunction viewed from bench and bedside (Part II)

Regioselective Friedel−Crafts Alkylation of Anilines and Amino‐Substituted Heteroarenes with Hexafluoroacetone Sesquihydrate

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