- Discovery of N-Alkyl Catecholamides as Selective Phosphodiesterase-4 Inhibitors with Anti-neuroinflammation Potential Exhibiting Antidepressant-like Effects at Non-emetic Doses
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Depression involving neuroinflammation is one of the most common disabling and life-threatening psychiatric disorders. Phosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utilit
- Zhou, Zhong-Zhen,Cheng, Yu-Fang,Zou, Zheng-Qiang,Ge, Bing-Chen,Yu, Hui,Huang, Cang,Wang, Hai-Tao,Yang, Xue-Mei,Xu, Jiang-Ping
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- Development of highly potent phosphodiesterase 4 inhibitors with anti-neuroinflammation potential: Design, synthesis, and structure-activity relationship study of catecholamides bearing aromatic rings
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In this study, catecholamides (7a–l) bearing different aromatic rings (such as pyridine-2-yl, pyridine-3-yl, phenyl, and 2-chlorophenyl groups) were synthesized as potent phosphodiesterase (PDE) 4 inhibitors. The inhibitory activities of these compounds w
- Zhou, Zhong-Zhen,Ge, Bing-Chen,Zhong, Qiu-Ping,Huang, Chang,Cheng, Yu-Fang,Yang, Xue-Mei,Wang, Hai-Tao,Xu, Jiang-Ping
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- Synthesis and evaluation of clioquinol-rolipram/roflumilast hybrids as multitarget-directed ligands for the treatment of Alzheimer's disease
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Considering the importance of PDE4D inhibition and the modulation of biometals in Alzheimer's disease (AD) therapeutics, we have designed, synthesized and evaluated a series of new clioquinol-rolipram/roflumilast hybrids as multitarget-directed ligands fo
- Hu, Jinhui,Pan, Tingting,An, Baijiao,Li, Zhengcunxiao,Li, Xingshu,Huang, Ling
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p. 512 - 526
(2019/01/03)
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- Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships
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In this study, a series of catechol-based amides (8a-n) with different amide linkers linking the catecholic moiety to the terminal phenyl ring was designed and synthesized as potent phosphodiesterase (PDE) 4D inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4B1 and PDE4D7 enzymes, and other PDE family members. The results indicated the majority of compounds 8a-n displayed moderate to good inhibitory activities against PDE4CAT. Among these compounds, compound 8j with a short amide linker (-CONHCH2-) displayed comparable PDE4CAT inhibitory activity (IC50 = 410 nM) with rolipram. More interestingly, compound 8g, a potent and selective PDE4D inhibitor (IC50 = 94 nM), exhibited a 10-fold selectivity over the PDE4B subtypes and an over 1000-fold selectivity against other PDE family members. Docking simulations suggested that 8g forms three extra H-bonds with the N-H of residue Asn487 and two water molecules.
- Zhou, Zhong-Zhen,Ge, Bing-Chen,Chen, Yu-Fang,Shi, Xiu-Dong,Yang, Xue-Mei,Xu, Jiang-Ping
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p. 7332 - 7339
(2015/11/16)
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- Synthesis, biological evaluation, and molecular modeling of new 3-(cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2- oxoethyl) oxime (GEBR-7b) related phosphodiesterase 4D (PDE4D) inhibitors
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A new series of 3-(cyclopentyloxy)-4-methoxyphenyl derivatives, structurally related to our hit GEBR-4a (1) and GEBR-7b (2), has been designed by changing length and functionality of the chain linking the catecholic moiety to the terminal cycloamine portion. Among the numerous molecules synthesized, compounds 8, 10a, and 10b showed increased potency as PDE4D enzyme inhibitors with respect to 2 and a good selectivity against PDE4A4, PDE4B2, and PDE4C2 enzymes, without both cytotoxic and genotoxic effects. The ability to enhance cAMP level in neuronal cells was assessed for compound 8. SAR considerations, also confirmed by in silico docking simulations, evidenced that both chain and amino terminal function characterized by higher hydrophilicity are required for a good and selective inhibitor-catalytic pocket interaction.
- Brullo, Chiara,Massa, Matteo,Rocca, Massimo,Rotolo, Chiara,Guariento, Sara,Rivera, Daniela,Ricciarelli, Roberta,Fedele, Ernesto,Fossa, Paola,Bruno, Olga
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p. 7061 - 7072
(2014/11/07)
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- Catechol pyrazolinones as trypanocidals: Fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase B1
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Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modeling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC50 values down to 49 nM. The compounds also block parasite proliferation (e.g., VUF13525 (20b): T. brucei rhodesiense IC50 = 60 nM, T. brucei brucei IC50 = 520 nM, T. cruzi = 7.6 μM), inducing a typical multiple nuclei and kinetoplast phenotype without being generally cytotoxic. The mode of action of 20b was investigated with recombinantly engineered trypanosomes expressing a cAMP-sensitive FRET sensor, confirming a dose-response related increase of intracellular cAMP levels in trypanosomes. Our findings further validate the TbrPDEB family as antitrypanosomal target.
- Orrling, Kristina M.,Jansen, Chimed,Vu, Xuan Lan,Balmer, Vreni,Bregy, Patrick,Shanmugham, Anitha,England, Paul,Bailey, David,Cos, Paul,Maes, Louis,Adams, Emily,Van Den Bogaart, Erika,Chatelain, Eric,Ioset, Jean-Robert,Van De Stolpe, Andrea,Zorg, Stèphanie,Veerman, Johan,Seebeck, Thomas,Sterk, Geert Jan,De Esch, Iwan J. P.,Leurs, Rob
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p. 8745 - 8756
(2013/01/15)
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- NEW HETEROCYCLIC AMIDE COMPOUNDS USEFUL FOR THE TREATMENT OF INFLAMMATORY AND ALLERGIC DISORDERS: PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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The present invention relates to novel heterocyclic compounds that inhibit phosphodiesterase type 4 (PDE 4). The compounds are useful for treating inflammatory conditions, diseases of the central nervous systems and insulin resistant diabetes.
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- Synthesis and biological evaluation of neutrophilic inflammation inhibitors
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In several non-infectious human diseases, such as ulcerous colitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), the extravasal recruitment of neutrophils plays a crucial role in the development of tissue damage, which, when persist
- Bruno, Olga,Brullo, Chiara,Arduino, Nicoletta,Schenone, Silvia,Ranise, Angelo,Bondavalli, Francesco,Ottonello, Luciano,Dapino, Patrizia,Dallegri, Franco
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p. 223 - 235
(2007/10/03)
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- Phthalazine derivatives as phosphodiesterase 4 inhibitors
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Compounds of formula (I) wherein B is alkylene, amino, CONH or a bond; Cy is optionally substituted phenyl or heteroaryl; R is H, phenyl or (C1-4)alkyl optionally substituted; R1is (C1-6)alkyl or polyfluoro(C1-6)-alkyl; R2is (C4-7)cycloalkyl optionally containing an oxygen atom and optionally substituted; and the N→O derivatives and pharmaceutically acceptable salt thereof are PDE 4 and TNFα inhibitors.
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- Phthalazine derivatives as phosphodiesterase 4 inhibitors
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The present invention provides a compound selected from the group including: N-3-acetyl-1-(3,5-dichloropyridin-4-ylmethyl)-5-cyclopentyloxy-6-methoxy-4H-phthalazine; 6,7-dimethoxy-1-pyridin-4-ylmethyl-4-thiazol-2-yl-phthalazine; 1-(6,7-dimethoxy-4-pyridin-4-ylmethyl-1H-phthalazin-2-yl)ethanone; 2-methanesulphonyl-6,7-dimethoxy-4-pyridin-4-ylmethyl-1,2-dihydrophthalazine; 2-formyl-6,7-dimethoxy-4-pyridin-4-ylmethyl-1,2-dihydrophthalazine; 1-(6,7-dimethoxy-4-pyridin-4-ylmethyl-1H-phthalazin-2-yl)-1-imidazol-1-ylmethanone; 1-(3,5-dichloro-pyridin-4-ylmethyl)-3-methansulphonyl-6-difluoromethoxy-5-(tetrahydro-furan-2-yloxy)-4H-phthalazine; N→O derivatives thereof; and pharmaceutically acceptable salts thereof. The invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the above compound in admixture with a pharmaceutically acceptable carrier.
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Page column 11-12
(2010/11/30)
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- Cathecol derivatives and a method for the preparation thereof and a pharmaceutical composition containing the same
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A phosphodiesterase IV inhibiting cathecol derivatives of the general formula I: or a pharmaceutically acceptable salt thereof in which R1 is C1-7 alkyl; C3-7 cycloalkane; phenyl optionally substituted with lower alkyl lower alkoxy, nitro or halogen; pyrimidine optionally substituted with lower alkyl, lower alkoxy, nitro or halogen; or pyridine optionally substituted with lower alkyl, lower alkoxy, nitro or halogen; X, Y and Z are each independently oxygen, nitrogen or sulfur optionally substituted with C1-7 alkyl, C3-7 cycloalkane or phenyl; W is oxygen or sulfur is disclosed. In addition, a process for producing the compound of the general formula I and a pharmaceutical composition containing pharmaceutically effective amount of the compound of the general formula I are disclosed.
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- COMPOUNDS CONTAINING PHENYL LINKED TO ARYL OR HETEROARYL BY AN ALIPHATIC- OR HETEROATOM-CONTAINING LINKING GROUP
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This invention is directed to the pharmaceutical use of phenyl compounds, which are linked to an aryl moiety by various linkages, for inhibiting tumor necrosis factor. The invention is also directed to the compounds, their preparation and pharmaceutical compositions containing these compounds. Furthermore, this invention is directed to the pharmaceutical use of the compounds for inhibiting cyclic AMP phosphodiesterase
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- Process development of the PDE IV inhibitor 3-(cyclopentyloxy)-n-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide
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Development of an industrial process for 3-(cyclopentyloxy)-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide, a potent PDE IV type inhibitor, is described. The rapid identification of scalable reaction conditions allowed pilot-scale synthesis of kilogramme quantities for early clinical evaluation. However, as more compound was demanded, better reaction conditions were required in the interests of safety, economics, and environmental impact. This led to the derivation of a high-yielding and very robust procedure which included various safeguards to ensure that high-quality product was obtained and that new trace impurities were effectively removed. The large-scale oxidation of a benzaldehyde derivative to the corresponding benzoic acid using hydrogen peroxide under aqueous alkaline conditions is described.
- Cook, David C.,Jones, Ronald H.,Kabir, Humayun,Lythgoe, David J.,McFarlane, Ian M.,Pemberton, Clive,Thatcher, Alan A.,Thompson, David M.,Walton, John B.
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p. 157 - 168
(2013/09/08)
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- Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic-or heteroatom-containing linking group
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This invention is directed to the pharmaceutical use of phenyl compounds, which are linked to an aryl moiety by various linkages, for inhibiting tumor necrosis factor. The invention is also directed to the compounds, their preparation and pharmaceutical compositions containing these compounds. Furthermore, this invention is directed to the pharmaceutical use of the compounds for inhibiting cyclic AMP phosphodiesterase.
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- Selective Type IV Phosphodiesterase Inhibitors as Antiasthmatic Agents. The Syntheses and Biological Activities of 3-(Cyclopentyloxy)-4-methoxybenzamides and Analogues
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The syntheses and biological activities of a number of benzamide derivatives, designed from rolipram, which are selective inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), are described.The effects of changes to the alkoxy groups, amide linkag
- Ashton, Michael J.,Cook, David C.,Fenton, Garry,Karlsson, Jan-Anders,Palfreyman, Malcolm N.,et al.
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p. 1696 - 1703
(2007/10/02)
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