- Synthesis and assessment of catechol diether compounds as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1)
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Human African trypanosomiasis (HAT) is a parasitic neglected tropical disease that affects 10,000 patients each year. Current treatments are sub-optimal, and the disease is fatal if not treated. Herein, we report our continuing efforts to repurpose the human phosphodiesterase 4 (hPDE4) inhibitor piclamilast to target trypanosomal phosphodiesterase TbrPDEB1. We prepared a range of substituted heterocyclic replacements for the 4-amino-3,5-dichloro- pyridine headgroup of piclamilast, and found that these compounds exhibited weak inhibitory activity of TbrPDEB1.
- Woodring, Jennifer L.,Bland, Nicholas D.,Ochiana, Stefan O.,Campbell, Robert K.,Pollastri, Michael P.
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- Enantioselective Flow Synthesis of Rolipram Enabled by a Telescoped Asymmetric Conjugate Addition-Oxidative Aldehyde Esterification Sequence Using in Situ-Generated Persulfuric Acid as Oxidant
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A novel approach is reported for the enantioselective flow synthesis of rolipram comprising a telescoped asymmetric conjugate addition-oxidative aldehyde esterification sequence followed by trichlorosilane-mediated nitro group reduction and concomitant la
- Nagy, Bence S.,Llanes, Patricia,Pericas, Miquel A.,Kappe, C. Oliver,?tv?s, Sándor B.
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- Synthesis of a TNF inhibitor, flurbiprofen and an: I -Pr analogue in enantioenriched forms by copper-catalyzed propargylic substitution with Grignard reagents
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The copper-catalyzed substitution reaction of diethyl phosphate derived from TMSCCCH(OH)CH2CH2OTBDPS with 3-c-C5H9-4-MeOC6H3MgBr, followed by several transformations, afforded a tumor necrosis factor inhibitor possessing a Ph-acetylene moiety. The inhibitor was also synthesized from phenylacetylene phosphate PhCCCH(OP(O)(OEt)2)CH2CH2OTBDPS. Furthermore, the substitution of phosphates derived from TMSCCCH(OH)CH3 and TMSCCCH(OH)-i-Pr with 3-F-4-PhC6H3MgBr gave the corresponding substitution products, which were transformed to flurbiprofen and its i-Pr analogue, respectively. The copper-catalyzed substitutions in these syntheses proceeded in a regio- and stereoselective manner. This journal is
- Isogawa, Yukari,Kobayashi, Yuichi,Ogawa, Narihito,Takashima, Yuji,Tsuboi, Atsuki
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supporting information
p. 9906 - 9909
(2021/12/07)
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- Synthesis of 1-[3-(Cyclopentyloxy)-4-methoxyphenyl]cyclopentanol as potential phosphodiesterase-4 inhibitor
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The enzyme phosphodiesterase-4 (PDE4) plays a key role in many physiological or pathological processes in mammalian organs, where its inhibition increases cyclic adenosine monophosphate (cAMP) causing benefits in many diseases or conditions. The aim of this study is to synthesize 1-(3-(cyclopentyloxy)-4-methoxyphenyl)cyclopentanol (6) as potential phosphodiesterase-4 inhibitor. Starting from 2- methoxy phenol (1), 4-bromo-2-(cyclopentyloxy)-1-methoxybenzene (5) was synthesized in good yields. 1-[3-(Cyclopentyloxy)-4- methoxyphenyl]cyclopentanol (6) was prepared from 5 using two different methods.
- Yahya-Meymandi,Mohammadi Ziarani,Shafiee,Foroumadi
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experimental part
p. 4008 - 4010
(2012/01/13)
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- Co-catalyzed reductive cyclization of azido and cyano substituted α,β-unsaturated esters with NaBH4: enantioselective synthesis of (R)-baclofen and (R)-rolipram
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Sodium borohydride in combination with a catalytic amount of CoCl2 has been found to be an excellent catalytic system in reductive cyclizations of suitably substituted azido and cyano groups of α,β-unsaturated esters to afford γ and δ-lactams in high yields. The process has been demonstrated for the enantioselective synthesis of (R)-baclofen, (R)-rolipram, and (R)-4-fluorophenylpiperidinone, a key intermediate for (-)-paroxetine.
- Paraskar, Abhimanyu S.,Sudalai, Arumugam
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p. 4907 - 4916
(2007/10/03)
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- Process and intermediates for making 4-cyanosubstituted cyclohexanoic acids
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Herein is provided a process for preparing substituted cyclohexanoic acids of formula (I), where Rais a carbon-containing group optionally linked by oxygen, sulfur or nitrogen to the phenyl ring and j is 1-5; and one of R and R* is hydrogen and the other is C(O)OH.
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- Novel selective PDE4 inhibitors. 2. Synthesis and structure-activity relationships of 4-aryl-substituted cis-tetra- and cis-hexahydrophthalazinones
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A series of 4-aryl-substituted cis-4a,5,8,8a-tetra- and cis-4a,5,6,7,8,8a-hexahydro-2H-phthalazin-1-ones with high inhibitory activity toward cAMP-specific phosphodiesterase (PDE4) was synthesized. To study structure-activity relationships various substituents were introduced to the 2-, 3-, and 4-positions of the 4-phenyl ring. Substitution at the 4-position of the phenyl ring was restricted to a methoxy group, probably due to unfavorable steric interactions of larger groups with the binding site. The introduction of many alkoxy substituents including distinct ring systems and functional groups was allowed to the 3-position. It was found that in general the cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are more potent than their hexahydrophthalic counterparts, the best activity residing in (4-imidazol-1-yl-phenoxy)butoxy analogue 16o (pIC50 = 9.7).
- Van der Mey,Hatzelmann,Van Klink,Van der Laan,Sterk,Thibaut,Ulrich,Timmerman
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p. 2523 - 2535
(2007/10/03)
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- Substituted β-thiocarboxylic acids
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This invention relates to compounds of general formula (I): in which Ar is a group selected from: A1, A2, B, C, D, E, Q1-Q3, R1-R9, Z1and Z2are as defined in the disclosure, and Y represents carboxy or an acid bioisostere. These compounds inhibit the production or physiological effects of TNF and inhibit cyclic AMP phosphodiesterase. The invention is also directed to pharmaceutical compositions comprising compounds of formula (I), their pharmaceutical use and methods for their preparation.
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- Synthesis of SB 222618. A potential PDE IV inhibitor
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PDE IV inhibitor SB 222618 was prepared by regioselective S(N)2' addition of 9 to bromoallene 6a followed by a stereoselective borane reduction of 4 to afford 2 which by a palladium mediated coupling with 3, delivered SB 222618 (1) in good yield. (C) 2000 Elsevier Science Ltd.
- Conde, Jose J.,Mendelson, Wilford
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p. 811 - 814
(2007/10/03)
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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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- Quaternary substituted PDE4 inhibitors I: The synthesis and in vitro evaluation of a novel series of oxindoles
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The following letter presents the synthesis and in vitro evaluation of a novel quaternary substituted series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds represent conformationally constrained analogues of the Celltech PDE IV inhibitor, CDP 840. Examples with sub-micromolar IC50's for PDE4 inhibition are reported.
- Hulme, Christopher,Poli, Gregory B.,Huang, Fu-Chih,Souness, John E.,Djuric, Stevan W.
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p. 175 - 178
(2007/10/03)
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- Substituted biphenyl derivatives
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A compound of the following structure: STR1 wherein, when R8 =H: R1 =alkyl, cycloalkyl, arylalkyl, aryl; R2 =cycloalkyl, aryl, C3 -C10 alkyl; X,Y=O, S(O)n, NH; Z=CHO, CO2 R3
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- Substituted biphenyl derivatives
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A compound of the following structure: STR1 wherein R8 =H: R1 =alkyl, cycloalkyl, arylalkyl, aryl; R2 =cycloalkyl, aryl, C3 -C10 alkyl; X,Y=O, S(O)n, NH; Z=CO2 R3, C(O
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- Biarylcarboxamide inhibitors of phosphodiesterase IV and tumor necrosis factor-
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Tumor necrosis factor-α (TNF-α) has been implicated as a key mediator in the progression of rheumatoid arthritis. Inhibitors of phosphodiesterase IV (PDE IV) have been shown to inhibit the production of TNF-α by elevating intracellular levels of cyclic adenosine monophosphate (cAMP). Our efforts in a series of biarylcarboxamides have led to the identification of 8j (CP-353,164) as a potent inhibitor of PDE IV and TNF-α production.
- Chambers,Marfat,Cheng,Cohan,Damon,Duplantier,Hibbs,Jenkinson,Johnson,Kraus,Pettipher,Salter,Shirley,Umland
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p. 739 - 744
(2007/10/03)
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- A stereoselective synthesis of (R)-(-)-rolipram from L-glutamic acid
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A stereoselective synthesis of (R)-(-)-rolipram from L-glutamic acid is described. The key step is a stereoselective Michael addition of an arylcuprate to a modified pyroglutamic derivative which acts as the template to induce the stereoselectivity. Facile manipulation of the enantiomerically pure Michael product afforded the expected therapeutic agent.
- Diaz, Adolfo,Siro, Jorge G.,García-Navío, José L.,Vaquero, Juan J.,Alvarez-Builla, Julio
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p. 559 - 562
(2007/10/03)
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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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- 1-Alkoxy-2-(alkoxy- or cycloalkoxy-)-4-(cyclothioalkyl- or cyclothioalkenyl-) benzenes as inhibitors of cyclic AMP phosphodiesterase and tumor necrosis factor
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This invention is directed to 1-alkoxy-2-(alkoxy- or cycloalkyloxy-)-4-(cyclothioalkyl- or cyclothioalkenyl-)benzene compounds that inhibit cyclic AMP phosphodiesterase or tumor necrosis factor (TNF) and are useful in treating patients suffering from disease state capable of being modulated by inhibiting production of cyclic AMP phosphodiesterase or TNF by administering the compound to the patient. The invention is also directed to the preparation of these compounds, pharmaceutical compositions containing these compounds and methods for their pharmaceutical use.
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- Biarylcarboxylic acids and -amides: Inhibition of phosphodiesterase type IV versus [3H]rolipram binding activity and their relationship to emetic behavior in the ferret
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In addition to having desirable inhibitory effects on inflammation, anaphylaxis, and smooth muscle contraction, PDE-IV inhibitors also produce undesirable side effects including nausea and vomiting. In general, compounds that inhibit PDE-IV also potently displace [3H]rolipram from a high-affinity binding site in rat cortex. While this binding site has not been identified, it has been proposed to be an allosteric binding site on the PDE-IV enzyme. Preliminary studies have suggested that the emetic potency of PDE-IV inhibitors is correlated with affinity for the brain rolipram binding site rather than potency at inhibiting PDE-IV enzyme activity. Efforts to eliminate the emetic potential of PDE-IV inhibitors were directed toward developing compounds with decreased [3H]rolipram binding affinity while retaining PDE-IV potency. Thus, a novel series of 4-(3-alkoxy-4- methoxyphenyl)benzoic acids and their corresponding carboxamides were prepared and evaluated for their PDE-IV inhibitory and rolipram binding site properties. Modification of the catechol ether moiety led to phenylbutoxy and phenylpentoxy analogues that provided the desired activity profile. Specifically, 4-[3-(5-phenylpentoxy)-4-methoxyphenyl]-2-methylbenzoic acid, 18, was found to exhibit potent PDE-IV inhibitory activity (IC50 0.41 μM) and possessed 400 times weaker activity than rolipram for the [3H]rolipram binding site. In vivo, compound 18 was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 8.8 mg/kg, po) and demonstrated a significant reduction in emetic side effects (ferret, 20% emesis at 30 mg/kg, po).
- Duplantier, Allen J.,Biggers, Michael S.,Chambers, Robert J.,Cheng, John B.,Cooper, Kelvin,Damon, David B.,Eggler, James F.,Kraus, Kenneth G.,Marfat, Anthony,Masamune, Hiroko,Pillar, Joann S.,Shirley, John T.,Umland, John P.,Watson, John W.
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p. 120 - 125
(2007/10/03)
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- PHENYL-SUBSTITUTED CYCLOALKENYL COMPOUNDS USEFUL AS PDE IV INHIBITORS
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A compound of formula (I) or a pharmaceutically acceptable salt thereof: STR1 wherein: R 1 is--CH 3 or--CH 2 CH. sub.3 unsubstituted or substituted by 1 to 3 fluorines; X is O or S(O) s where s=0 to 2;R 2 is C 4-C 6 cyclic alkyl, optionally substituted by one to three methyl groups or one ethyl group;--CH 2-cyclopentyl,--CH 2-cyclopropyl, 3-tetrahydrofuranyl, C 1-7 alkyl, CH 3 or CH 2 CH 3 substituted by one to three fluorines;--(CH. sub.2) n COO(CH 2) g CH. sub.3, or (CH 2) n O(CH 2) g CH. sub.3, wherein n is 2 to 4 and g is 0 to 2; R 3 represents a moiety of formula (a); STR2 wherein R 4 and R 5 each represent hydrogen or R 4 and R 5 together represent a bond; B represents > C=O, > C=S or > CH--R. sub.6 wherein R 6 represents H, OH, C 1-6 alkoxy or C. sub.1-6 thioalkoxy; and m and r each independently represents zero or an integer in the range of 1 to 4 wherein m+r represents an integer in the range of from 2 to 4; with the proviso that when R 1 is methyl, X is oxygen, R. sub.2 is methyl or cyclopenyl, R 3 does not represent cyclopent-1,2-ene-3-one.
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- The Synthesis of Aracemic 4-Substituted Pyrrolidinones and 3-Substituted Pyrrolidines. An Asymmetric Synthesis of (-)-Rolipram
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Conjugate additions of RCuCNLi to the chiral α,β-unsaturated lactam 4 gives almost exclusive exo addition - a reversal in stereochemistry when cuprates were added to chiral lactam 1.The lactams 5 were transformed into 4-substituted pyrrolidinones 8 via a three-step sequence which involved decarbalkoxylation, silane reduction and metal-ammonia benzylamine cleavage.The chemical yields as well as the enantiomeric purity were very high for this process.As an example of the usefulness of this scheme, the antidepressant (-)-Rolipram was prepared in good overall yield.Furthermore, the bicyclic lactams 6 were readily transformed, using alane as the reducing agent, to 3-substituted pyrrolidines 11.Absolute configurations of 8 and 11 were confirmed by comparison with literature assignments which also gave strong support to the facial addition of the cuprates to 4.
- Meyers, A. I.,Snyder, Lawrence
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