- Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors
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Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The (S)-Zl-n-91 enantiomer showed IC50 values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that (S)-Zl-n-91 but not (R)-Zl-n-91 formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for the design of PDE4 selective inhibitors.
- Feng, Xiaoqing,Wang, Huanchen,Ye, Mengchun,Xu, Xue-Tao,Xu, Ying,Yang, Wenzhe,Zhang, Han-Ting,Song, Guoqiang,Ke, Hengming
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Read Online
- Diastereoselective synthesis and profiling of bicyclic imidazolidinone derivatives bearing a difluoromethylated catechol unit as potent phosphodiesterase 4 inhibitors
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Metal-mediated C-H functionalization of cyclic N-oxides was exploited to access a series of new difluoromethylated analogs of imidazolidinone-based PDE4 inhibitor CMPI in a diastereoselective manner. Among the products synthesized, compounds with fine-tuned activity/selectivity profiles compared to both CMPI and the clinically applied apremilast were identified. From these studies, an unusual fused 1,2-oxazinoimidazolidinone heterocyclic system was suggested as a novel scaffold for the design of potent and selective PDE4 inhibitors. Computational studies suggest that the oxygen atom in the imidazolidinone unit can bind to the metal ion center (most likely Mg2+). DFT calculations of the relative interaction energies of inhibitors with Mg2+ and Zn2+ ions were performed on a model of the bimetal active site of PDE4.
- Dorokhov, Valentin S.,Golovanov, Ivan S.,Tartakovsky, Vladimir A.,Sukhorukov, Alexey Yu.,Ioffe, Sema L.
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Read Online
- Insight into GEBR-32a: Chiral resolution, absolute configuration and enantiopreference in PDE4D inhibition
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Alzheimer's disease is the most common type of dementia, affecting millions of people worldwide. One of its main consequences is memory loss, which is related to downstream effectors of cyclic adenosine monophosphate (cAMP). A well-established strategy to avoid cAMP degradation is the inhibition of phosphodiesterase (PDE). In recent years, GEBR-32a has been shown to possess selective inhibitory properties against PDE type 4 family members, resulting in an improvement in spatial memory processes without the typical side effects that are usually correlated with this mechanism of action. In this work, we performed the HPLC chiral resolution and absolute configuration assignment of GEBR-32a. We developed an efficient analytical and semipreparative chromatographic method exploiting an amylose-based stationary phase, we studied the chiroptical properties of both enantiomers and we assigned their absolute configuration by 1H-NMR (nuclear magnetic resonance). Lastly, we measured the IC50 values of both enantiomers against both the PDE4D catalytic domain and the long PDE4D3 isoform. Results strongly support the notion that GEBR-32a inhibits the PDE4D enzyme by interacting with both the catalytic pocket and the regulatory domains.
- Brullo, Chiara,Bruno, Olga,Cavalloro, Valeria,Collina, Simona,Donini, Stefano,Parisini, Emilio,Pignataro, Luca,Rapetti, Federica,Rossi, Daniela,Russo, Katia,Semrau, Marta S.,Storici, Paola,Torretta, Archimede,Vasile, Francesca
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Read Online
- Redox-Neutral TEMPO Catalysis: Direct Radical (Hetero)Aryl C?H Di- and Trifluoromethoxylation
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Applications of TEMPO. catalysis for the development of redox-neutral transformations are rare. Reported here is the first TEMPO.-catalyzed, redox-neutral C?H di- and trifluoromethoxylation of (hetero)arenes. The reaction exhibits a broad substrate scope, has high functional-group tolerance, and can be employed for the late-stage functionalization of complex druglike molecules. Kinetic measurements, isolation and resubjection of catalytic intermediates, UV/Vis studies, and DFT calculations support the proposed oxidative TEMPO./TEMPO+ redox catalytic cycle. Mechanistic studies also suggest that Li2CO3 plays an important role in preventing catalyst deactivation. These findings will provide new insights into the design and development of novel reactions through redox-neutral TEMPO. catalysis.
- Lee, Johnny W.,Lim, Sanghyun,Maienshein, Daniel N.,Liu, Peng,Ngai, Ming-Yu
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supporting information
p. 21475 - 21480
(2020/10/02)
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- Drug compound for treating hepatopathy and application thereof
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The invention discloses a drug compound for treating hepatopathy and application thereof. The drug compound specifically serves as a compound shown in general formula (I) or an optical isomer or a pharmaceutically-acceptable salt of the compound. The compound or the optical isomer or the pharmaceutically-acceptable salt of the compound has a good curative effect and low toxicity on hepatopathy, especially fatty liver. Experiments show that the compound has an obvious protective effect on zebrafish nonalcoholic fatty liver, so that the drug compound has a good application prospect in medicinesfor treatment or prevention of hepatopathy, especially fatty liver or liver fibrosis or liver cirrhosis.
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- Catalytic radical difluoromethoxylation of arenes and heteroarenes
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Intermolecular C-H difluoromethoxylation of (hetero)arenes remains a long-standing and unsolved problem in organic synthesis. Herein, we report the first catalytic protocol employing a redox-active difluoromethoxylating reagent 1a and photoredox catalysts for the direct C-H difluoromethoxylation of (hetero)arenes. Our approach is operationally simple, proceeds at room temperature, and uses bench-stable reagents. Its synthetic utility is highlighted by mild reaction conditions that tolerate a wide variety of functional groups and biorelevant molecules. Experimental and computational studies suggest single electron transfer (SET) from excited photoredox catalysts to 1a forming a neutral radical intermediate that liberates the OCF2H radical exclusively. Addition of this radical to (hetero)arenes gives difluoromethoxylated cyclohexadienyl radicals that are oxidized and deprotonated to afford the products of difluoromethoxylation.
- Lee, Johnny W.,Zheng, Weijia,Morales-Rivera, Cristian A.,Liu, Peng,Ngai, Ming-Yu
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p. 3217 - 3222
(2019/03/21)
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- DIFLUOROMETHOXYLATION AND TRIFLUOROMETHOXYLATION COMPOSITIONS AND METHODS FOR SYNTHESIZING SAME
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The present invention provides a compound having the structure (I), a processing of making the compound; and a process of using the compound as a reagent for the difluoromethoxylation and trifluoromethoxylation of arenes or heteroarenes.
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Page/Page column 75; 79; 89; 98-99
(2019/09/18)
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- A method for preparing raw material for roflumilast and detection method
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The invention discloses a preparation method and a detection method of a roflumilast material. The preparation method comprises the following steps: mixing 3-cyclopropyl methoxy group-4-difluoro methoxy group benzoic acid SM-1, thionyl chloride, dimethyl formamide with toluene, and carrying out an acylating chlorination reaction to obtain a midbody 1; mixing 3,5-dichloro-4-aminopyridine SM-2, tetrahydrofuran with potassium tert-butoxide and carrying out a salt forming reaction to obtain tetrahydrofuran solution of a midbody 2; and then mixing the midbody 1 and the midbody 2 with tetrahydrofuran, carrying out amidation to obtain a crude product of roflumilast, and refining the crude product of roflumilast to prepare the roflumilast material. Aiming to overcome the shortage of the prior art, the preparation process of the roflumilast material is optimized, so that the curative effect for treating diseases such as chronic obstructive pulmonary disease (COPD) is more remarkable; and besides, a systematic, complete and effective composition identifying and content measuring method is provided, so that the quality of the medicine can be effectively controlled, and the clinical effect is ensured.
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Paragraph 0020-0021; 0277-0278
(2018/05/16)
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- Synthesis method of roflumilast key intermediate
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The invention discloses a synthesis method of a roflumilast key intermediate. Specifically speaking, the synthesis method comprises the following steps: (1) preparing 3-methoxy-4-difluoro methoxybenzaldehyde; (2) preparing 3-hydroxy-4-difluoro methoxybenzaldehyde; (3) preparing 3-cyclopropyl methoxy-4-difluoro methoxybenzaldehyde; (4) preparing 3-cyclopropyl methoxy-4-difluoro methoxybenzoic acid. Compared with the existing synthesis method, the synthesis method disclosed in the invention has the advantages that low-price raw materials are adopted, thereby greatly reducing the production cost; vanillin serves as a starting material, thereby avoiding generation of similar impurities; column chromatography is replaced with recrystallization which serves as a purification way, thereby facilitating large-scale production application, and the yield and the purity are higher.
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Paragraph 0038; 0043-0045
(2017/07/21)
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- Synthesis method of 3-hydroxyl-4-difluoromethoxyl benzaldehyde
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The invention discloses a synthesis method of 3-hydroxyl-4-difluoromethoxyl benzaldehyde. According to the synthesis method, 3,4-dihydroxyl benzaldehyde is taken as the raw material, solid sodium chlorodifluoroacetate is taken as the difluoro-methylation reagent, 3-hydroxyl-4-difluoromethoxyl benzaldehyde can be obtained in the presence of alkali, the yield is high, and 3-hydroxyl-4-difluoromethoxyl benzaldehyde is an important intermediate for Roflumilast synthesis.
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Paragraph 0034; 0039; 0040
(2017/03/22)
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- Preparation method for high-purity roflumilast
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The invention belongs to the technical field of medicine, and particularly relates to a preparation method for high-purity roflumilast and an intermediate 3-hydroxy-4-diflouromethylbenzaldehyde of the roflumilast. The preparation method comprises the steps that the 3-hydroxy-4-diflouromethylbenzaldehyde is firstly obtained by taking 3-hydroxy-4-dihydroxybenzaldehyde as raw materails at higher yield and purity and then synthesized into 3-cyclopropylmethoxy-4-diflouromethylbenzaldehyde, the 3-cyclopropylmethoxy-4-diflouromethylbenzaldehyde is oxidized to obtain 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, and finally the 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid reacts with 4-amino-3,5-dichloropyridine to obtain the roflumilast. Due to the fact that the 3-hydroxy-4-diflouromethylbenzaldehyde with the higher yield and purity is obtained, the total yield of the roflumilast is increased, and many by-products which are difficult to separate cannot be generated.
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Paragraph 0035; 0036
(2016/10/10)
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- Preparation method for roflumilast intermediates
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The invention discloses a preparation method for roflumilast intermediates. The preparation method includes: 1), adding 3, 4-dihydroxybenzaldehyde and methyl bromodifluoroacetate into acetonitrile for contact reaction at the temperature of 30-45 DEG C in the presence of hydroxylamine, adding water after reaction completion, extracting and concentrating dichloromethane, and performing petroleum ether recrystallization to obtain 3-hydroxy-4-diflouromethylbenzaldehyde; 2), adding the 3-hydroxy-4-diflouromethylbenzaldehyde and bromomethyl cyclopropane into the acetonitrile for hybrid reaction in the presence of N-methylmorpholine and zinc salt at the temperature of 55-60 DEG C to obtain 3-cyclopropylmethoxy-4-(difluoromethoxy) benzaldehyde; 3), subjecting the 3-cyclopropylmethoxy-4-(difluoromethoxy) benzaldehyde and oxidizing agent comprising MnO2 and HClO to oxidation reaction at the temperature of 45-50 DEG C to obtain 3-cyclopropylmethoxy-4-(difluoromethoxy) benzoic acid. The preparation method has the advantages that selectivity is high and yield is increased; conditions are milder, influences on other groups are avoided and by-products are fewer.
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Paragraph 0023; 0031
(2016/10/10)
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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 activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors
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Abstract A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity.
- Brullo, Chiara,Massa, Matteo,Villa, Carla,Ricciarelli, Roberta,Rivera, Daniela,Pronzato, Maria Adelaide,Fedele, Ernesto,Barocelli, Elisabetta,Bertoni, Simona,Flammini, Lisa,Bruno, Olga
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supporting information
p. 3426 - 3435
(2015/08/03)
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- NEW COMPOUNDS HAVING A SELECTIVE PDE4D INHIBITING ACTIVITY
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Compounds of formula (I), wherein Z = cyclopentyl. cyclopropylmethyl, -CH3; R' = -CH3, CHF2, X= formula (II) (III) (IV) (V) Y = - CO; -C=O(CH2), -CH(OH)-CH2, -CH2-C=O, -CH2-CH2-C=O; -CH2-CH(OH)-CH2, -CH2- CH(OCOR1)-CH2 NR2 = -N(CH2-CH2OH)2, formula (VI) (VII) (VIII) (IX) (X) (XI) R1 = optionally substituted C1-C8 alkyl, optionally substituted aryl; optionally substituted aralkyl, preferably C1-C3 alkyl, more preferably CH3; and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof; these compounds have a PDE4D inhibiting activity and can be used as a medicament for treating dementia, in particular Alzheimer disease, and for improving memory.
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Paragraph 46-47
(2015/09/22)
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- PROCESS FOR THE PREPARATION OF ROFLUMILAST
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The present invention relates to an improved process for the preparation of Roflumilast. The present invention also relates to crystalline Form-I of Roflumilast.
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Paragraph 0051
(2014/09/30)
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- Novel class of benzoic acid ester derivatives as potent PDE4 inhibitors for inhaled administration in the treatment of respiratory diseases
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The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4- yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.
- Armani, Elisabetta,Amari, Gabriele,Rizzi, Andrea,Fanti, Renato De,Ghidini, Eleonora,Capaldi, Carmelida,Carzaniga, Laura,Caruso, Paola,Guala, Matilde,Peretto, Ilaria,La Porta, Elena,Bolzoni, Pier T.,Facchinetti, Fabrizio,Carnini, Chiara,Moretto, Nadia,Patacchini, Riccardo,Bassani, Franco,Cenacchi, Valentina,Volta, Roberta,Amadei, Francesco,Capacchi, Silvia,Delcanale, Maurizio,Puccini, Paola,Catinella, Silvia,Civelli, Maurizio,Villetti, Gino
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p. 793 - 816
(2014/03/21)
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- MONOCYCLIC PYRIDINE DERIVATIVE
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The present invention provides a novel compound having FGFR inhibitory activity or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same. Specifically, the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: wherein n represents 0 to 2; A represents an arylene group or a heteroarylene group; G represents a single bond, an oxygen atom or —CH2—; E represents a nitrogen-containing non-aromatic heterocycle; R1 represents an alkoxy group or the like; R2 represents a hydrogen atom or the like; and R3 represents a hydrogen atom, an alkyl group, an alkoxy group or the like, with the proviso that when E represents an azetidine ring and R2 or R3 is present on a nitrogen atom on the azetidine ring, the R2 or R3 does not represent a hydrogen atom.
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Paragraph 0470; 0471; 0472
(2014/09/03)
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- Novel roflumilast analogs as soft PDE4 inhibitors
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PDE4 inhibitors are of high interest for treatment of a wide range of inflammatory or autoimmune diseases. Their potential however has not yet been realized due to target-associated side effects, resulting in a low therapeutic window. We herein report the design, synthesis and evaluation of novel PDE4 inhibitors containing a γ-lactone structure. Such molecules are designed to undergo metabolic inactivation when entering circulation, thereby limiting systemic exposure and reducing the risk for side effects. The resulting inhibitors were highly active on both PDE4B1 and PDE4D2 and underwent rapid degradation in human plasma by paraoxonase 1. In contrast, their metabolites displayed markedly reduced permeability and/or on-target activity.
- Boland, Sandro,Alen, Jo,Bourin, Arnaud,Castermans, Karolien,Boumans, Nicki,Panitti, Laura,Vanormelingen, Jessica,Leysen, Dirk,Defert, Olivier
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supporting information
p. 4594 - 4597
(2015/02/06)
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- 3′,4′-Bis-difluoromethoxycinnamoylanthranilate (FT061): An orally-active antifibrotic agent that reduces albuminuria in a rat model of progressive diabetic nephropathy
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Cinnamoylanthranilates including tranilast have been identified as promising antifibrotics that can reduce fibrosis occurring in the kidney during diabetes, thereby delaying and/or preventing kidney dysfunction. Structure-activity relationships aimed at improving potency and metabolic stability have led to the discovery of FT061. This compound, which bears a bis-difluoromethoxy catechol, attenuates TGF-β-stimulated production of collagen in cultured renal mesangial cells (approx 50% at 3 μM). When dosed orally at 20 mg/kg to male Sprague Dawley rats, FT061 exhibited a high bioavailability (73%), Cmax of 200 μM and Tmax of 150 min, and a half-life of 5.4 h. FT061 reduced albuminuria when orally dosed in rats at 200 mg kg/day in a late intervention study of a rat model of progressive diabetic nephropathy.
- Williams, Spencer J.,Zammit, Steven C.,Cox, Alison J.,Shackleford, David M.,Morizzi, Julia,Zhang, Yuan,Powell, Andrew K.,Gilbert, Richard E.,Krum, Henry,Kelly, Darren J.
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supporting information
p. 6868 - 6873
(2014/01/06)
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- NOVEL SOFT PDE4 INHIBITORS
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The present invention relates to new phosphodiesterase inhibitors, more specifically soft PDE4 inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new soft PDE4 inhibitors compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the invention relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including inflammatory diseases.
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Page/Page column 39; 40
(2013/03/26)
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- Synthesis and in vitro biological evaluation of novel 2-aminoimidazolone derivatives as anti-tumor agents
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Novel 2-aminoimidazolone derivatives were synthesized. Most compounds displayed strong anticancer activities against human carcinoma cells in vitro. Compounds 8a, 8b and 8j exhibited optimal activity superior to 5-FU in most cancer cells tested. Especially, the IC50s of 8b (12.6-21.5 μmol/L) against five tumor cells were 1-4 fold less than those of 5-FU (18.4-56.1 μmol/L) in vitro. Furthermore, compound 8b could induce SMMC-7721 cell apoptosis in a dose-dependent manner. Therefore, our novel findings may provide a new framework for the design of new 2-aminoimidazolone derivatives for the treatment of cancer.
- Xiao, You-An,Wang, Zhi-Qiang,Wang, Xue-Min,Hui, Yi,Ling, Yong,Wang, Xin-Yang,He, Li-Qin
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p. 727 - 730
(2013/07/26)
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- PHOSPHODIESTERASE INHIBITORS
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The present invention relates to phosphodiesterase (PDE) type IV selective inhibitors. Compounds disclosed herein can be useful in the treatment of CNS diseases, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans. Processes for the preparation of disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and their use as PDE type IV selective inhibitors, are provided.
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Page/Page column 9
(2010/03/02)
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- HETEROCYCLIC COMPOUNDS AS PHOSPHODIESTERASE INHIBITORS
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Described are compounds of the formula (I), their derivatives, analogs, tautomeric forms, regioisomers, stereoisomers, polymorphs, solvates, intermediates, pharmaceutically acceptable salts, pharmaceutical compositions, N-oxides, metabolites and prodrugs thereof. These compounds are phosphodiesterase type 4 (PDE4) inhibitors. They are useful in the treatment of a variety of allergic or inflammatory diseases including asthma, COPD, chronic bronchitis, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, vernal conjuctivitis, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, uveitis, NASH and lupus.
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Page/Page column 31
(2010/08/08)
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- HALOGENATED ANALOGUES OF ANTI-FIBROTIC AGENTS
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The present invention relates to halogenated compounds of formula (I) with the substituents as described within the specification. The compounds may be useful as anti-fibrqtic agents. The present invention also relates to methods for their preparation.
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Page/Page column 35
(2009/07/25)
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- Ester derivatives as phosphodiesterase inhibitors
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are new ester derivatives, methods of preparing such compounds, compositions containing them and therapeutic use thereof
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Page/Page column 21-22
(2009/07/10)
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- Design, synthesis, and structure - Activity relationship, molecular modeling, and NMR studies of a series of phenyl alkyl ketones as highly potent and selective phosphodiesterase-4 inhibitors
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Phosphodiesterase 4 catalyzes the hydrolysis of cyclic AMP and is a target for the development of anti-inflammatory agents. We have designed and synthesized a series of phenyl alkyl ketones as PDE4 inhibitors. Among them, 13 compounds were identified as having submicromolar IC50 values. The most potent compounds have IC50 values of in the mid- to low-nanomolar range. Compound 5v also showed preference for PDE4 with selectivity of >2000-fold over PDE7, PDE9, PDE2, and PDE5. Docking of 5v, 5zf, and 5za into the binding pocket of the PDE4 catalytic domain revealed a similar binding profile to PDE4 with rolipram except that the fluorine atoms of the difluoromethyl groups of 5v, 5za, and 5zf are within a reasonable range for hydrogen bond formation with the amide hydrogen of Thr 333 and the long alkyl chain bears additional van der Waals interactions with His 160, Asp 318, and Tyr 159.
- Zheng, Shilong,Kaur, Gurpreet,Wang, Huanchen,Li, Minyong,Macnaughtan, Megan,Yang, Xiaochuan,Reid, Suazette,Prestegard, James,Wang, Binghe,Ke, Hengming
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experimental part
p. 7673 - 7688
(2009/12/07)
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- Fluoroalkoxycombretastatin Derivatives, Method For Producing the Same and Use Thereof
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Combretastatin derivatives of formula (I), preparation and use thereof are disclosed, wherein: Rf is alkyl with 1-8 carbon atoms and 1-17 fluorine atoms, R is amino, substituted amino, hydroxyl, nitro, halo, alkyloxy, phosphate or amino acid side chain. Said derivatives have a capability to inhibit the polymerization of microtubules and are useful in treatment against tumor and neovascularization.
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Page/Page column 8
(2009/01/20)
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- NOVEL PROCESSES FOR PREPARING 6-(DIFLUOROMETHOXY) [1]BENZOFURO[3,2-C]PYRIDINE-9-CARBALDEHYDE, A NOVEL INTERMEDIATE FOR THE SYNTHESIS OF PDE IV INHIBITORS
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The present invention relates to novel processes for preparing 6-(difluoromethoxy)[1] benzofuro[3,2-c]pyridine-9-carbaldehyde, which is a novel and useful intermediate for preparing compounds with PDE4 inhibitory activity, such as 3,5-dichloro-4-(6- difluoromethoxybenzo[4,5] furo [3,2-c]pyridin-9-ylcarboxamido)-1 -pyridiniumolate
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Page/Page column 19
(2009/01/20)
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- Derivatives of 1-phenyl-2-pyridynyl alkylene alcohols as phosphodiesterase inhibitors
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridynyl alkylene alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 10
(2008/06/13)
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- Phosphodiesterase 4 inhibitors
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Selective PDE4 inhibition is achieved by aryl and heteroaryl pyrazole compounds. The compounds exhibit improved PDE4 inhibition as compared to compounds such as rolipram and show selectivity with regard to inhibition of other classes of PDEs.
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Page/Page column 36
(2010/11/28)
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- AZOLE-BASED PHOSPHODIESTERASE INHIBITORS
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The present invention relates to phosphodiesterase (PDE) type IV selective inhibitors. Processes for the preparation of disclosed compounds of Formula (I), pharmaceutical compositions containing the compounds described herein and their use as PDE type IV selective inhibitors are provided.
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Page/Page column 45
(2010/11/24)
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- PHOSPHODIESTERASE 4 INHIBITORS
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Selective PDE4 inhibition is achieved by aryl and heteroaryl pyrazole compounds. The compounds exhibit improved PDE4 inhibition as compared to compounds such as rolipram and show selectivity with regard to inhibition of other classes of PDEs.
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Page/Page column 111
(2010/11/08)
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- INHIBITORS OF PHOSPHODIESTERASE TYPE-IV
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The present invention relates to isoxazoline derivatives, which can be used as selective inhibitors of phosphodiesterase (PDE) type IV. In particular, compounds disclosed herein can be useful in the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases in a patient, particularly in humans. The present invention also relates to processes for the preparation of disclosed compounds, as well as pharmaceutical compositions thereof, and their use as phosphodiesterase (PDE) type IV inhibitors.
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Page/Page column 64-65
(2010/02/11)
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- PYRAZOLE DERIVATIVES AS PHOSPHODIESTERASE 4 INHIBITORS
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Selective PDE4 inhibition is achieved by aryl and heteroaryl pyrazole compounds. The compounds exhibit improved PDE4 inhibition as compared to compounds such as rolipram and show selectivity with regard to inhibition of other classes of PDEs.
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- Discovery of L-791,943: a potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor.
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Structure-activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (11n) as a potent (HWB TNF-alpha = 0.67 microM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey.
- Guay, Daniel,Hamel, Pierre,Blouin, Marc,Brideau, Christine,Chan, Chi Chung,Chauret, Nathalie,Ducharme, Yves,Huang, Zheng,Girard, Mario,Jones, Tom R,Laliberte, France,Masson, Paul,McAuliffe, Malia,Piechuta, Hanna,Silva, Jose,Young, Robert N,Girard, Yves
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p. 1457 - 1461
(2007/10/03)
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- Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: Prevention of reactive intermediate formation and covalent binding
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A detailed study directed towards metabolic stability optimization of the alkoxy substituents on the catechol moiety of CDP-840 is reported. Replacement of the methoxy and cyclopentyloxy substituents by cyclobutyloxy and/or difluromethoxy groups resulted in the discovery of potent and selective PDE4 inhibitors where the formation of reactive metabolites that could covalently bind to microsomal protein was significantly reduced or eliminated.
- Chauret, Nathalie,Guay, Daniel,Li, Chun,Day, Stephen,Silva, José,Blouin, Marc,Ducharme, Yves,Yergey, James A.,Nicoll-Griffith, Deborah A.
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p. 2149 - 2152
(2007/10/03)
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- Catechol diethers as selective PDE IV inhibitors
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This invention relates to 4-substituted catechol diether compounds which are selective inhibitors of phosphodiesterase (PDE) type IV. The compounds of the present invention are useful in inhibiting PDE IV and in the treatment of AIDS, asthma, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases. This invention also relates to pharmaceutical compositions comprising the compounds hereof
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- Method for synthesis of aryl difluoromethyl ethers
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This invention relates to a method for preparing difluoromethyl ethers, thiols and amines without using chlorofluorocarbon gases. The intermediates prepared by this method can be used to make certain compounds which act as PDE IV inhibitors which are useful for treating asthma and other diseases implicated with the PDE IV isozyme.
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- Compounds useful for treating allergic or inflammatory diseases
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Novel cyclohexanes of Formulas (I) and (II) STR1 are described herein. They inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease states mediated or exacerbated by TNF production; these compounds are also useful in the mediation or inhibition of enzymatic or catalytic activity of phosphodiesterase V.
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