Synthesis and biological evaluation of ranitidine analogs as multiple-target-directed cognitive enhancers for the treatment of Alzheimer's disease.


:Using molecular modeling and rationally designed structural modifications, the multi-target structure-activity relationship for a series of ranitidine analogs has been investigated. Incorporation of a variety of isosteric groups indicated that appropriate aromatic moieties provide optimal interactions with the hydrophobic and π-π interactions with the peripheral anionic site of the AChE active site. The SAR of a series of cyclic imides demonstrated that AChE inhibition is increased by additional aromatic rings, where 1,8-naphthalimide derivatives were the most potent analogs and other key determinants were revealed. In addition to improving AChE activity and chemical stability, structural modifications allowed determination of binding affinities and selectivities for M1-M4 receptors and butyrylcholinesterase (BuChE). These results as a whole indicate that the 4-nitropyridazine moiety of the JWS-USC-75IX parent ranitidine compound (JWS) can be replaced with other chemotypes while retaining effective AChE inhibition. These studies allowed investigation into multitargeted binding to key receptors and warrant further investigation into 1,8-naphthalimide ranitidine derivatives for the treatment of Alzheimer's disease.


Bioorg Med Chem Lett


Gao J,Midde N,Zhu J,Terry AV,McInnes C,Chapman JM




Has Abstract


2016-11-15 00:00:00














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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chu GH,Gu M,Cassel JA,Belanger S,Graczyk TM,DeHaven RN,Conway-James N,Koblish M,Little PJ,DeHaven-Hudkins DL,Dolle RE

    更新日期:2007-04-01 00:00:00

  • 4-Alkyl and 4,4'-dialkyl 1,2-bis(4-chlorophenyl)pyrazolidine-3,5-dione derivatives as new inhibitors of bacterial cell wall biosynthesis.

    abstract::Over 195 4-alkyl and 4,4-dialkyl 1,2-bis(4-chlorophenyl)pyrazolidine-3,5-dione derivatives were synthesized, utilizing microwave accelerated synthesis, for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good activity against MurB in vitro and low MIC values against gram-pos...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kutterer KM,Davis JM,Singh G,Yang Y,Hu W,Severin A,Rasmussen BA,Krishnamurthy G,Failli A,Katz AH

    更新日期:2005-05-16 00:00:00

  • Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17alpha-hydroxylase/17,20-lyase (P450(17alpha)).

    abstract::We report the preliminary results of the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of phenyl alkyl imidazole-based compounds as inhibitors of the two components of 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), that is, 17alpha-hydroxylase (17alpha-OHase) and 17,20-...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Patel CH,Dhanani S,Owen CP,Ahmed S

    更新日期:2006-09-15 00:00:00

  • Inhibition of human cytomegalovirus protease N(o) with monocyclic beta-lactams.

    abstract::Monocyclic beta-lactams have been identified as potent and selective inhibitors of the human cytomegalovirus protease (HCMV) N(o). Two series of these inhibitors are described, a peptidyl series of compounds and non-peptidic molecules featuring lower molecular weights. The SAR work that lead to the discovery of these ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Déziel R,Malenfant E

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  • Synthesis, spectroscopic studies and biological evaluation of acridine derivatives: The role of aggregation on the photodynamic efficiency.

    abstract::Two new photoactive compounds (1 and 2) derived from the 9-amidoacridine chromophore have been synthesized and fully characterized. Their abilities to produce singlet oxygen upon irradiation have been compared. The synthesized compounds show very different self-aggregating properties since only 1 present a strong tend...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Felip-León C,Martínez-Arroyo O,Díaz-Oltra S,Miravet JF,Apostolova N,Galindo F

    更新日期:2018-03-01 00:00:00

  • Synthesis and biological activity of pyridopyridazin-6-one p38α MAP kinase inhibitors. Part 2.

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tynebor RM,Chen MH,Natarajan SR,O'Neill EA,Thompson JE,Fitzgerald CE,O'Keefe SJ,Doherty JB

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Qi J,Zhu J,Liu X,Ding L,Zheng C,Han G,Lv J,Zhou Y

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Phillips RS,Anderson AD,Gentry HG,Güner OF,Bowen JP

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Gentile G,Di Fabio R,Pavone F,Sabbatini FM,St-Denis Y,Zampori MG,Vitulli G,Worby A

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hirokawa Y,Kinoshita H,Tanaka T,Nakamura T,Fujimoto K,Kashimoto S,Kojima T,Kato S

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Guan L,Luo Y,Ja WW,Disney MD

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Beaton H,Hamley P,Nicholls DJ,Tinker AC,Wallace AV

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  • O-arylmandelic acids as highly selective human PPAR alpha/gamma agonists.

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Adams AD,Hu Z,von Langen D,Dadiz A,Elbrecht A,MacNaul KL,Berger JP,Zhou G,Doebber TW,Meurer R,Forrest MJ,Moller DE,Jones AB

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zhang FF,Gan LL,Zhou CH

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Espinoza-Moraga M,Singh K,Njoroge M,Kaur G,Okombo J,De Kock C,Smith PJ,Wittlin S,Chibale K

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Seward EM,Carlson E,Harrison T,Haworth KR,Herbert R,Kelleher FJ,Kurtz MM,Moseley J,Owen SN,Owens AP,Sadowski SJ,Swain CJ,Williams BJ

    更新日期:2002-09-16 00:00:00

  • Identification of an indole series of prostaglandin D2 receptor antagonists.

    abstract::A novel indole series of PGD2 receptor (DP receptor) antagonists is presented. Optimization of this series led to the identification of potent and selective DP receptor antagonists. In particular, antagonists 35 and 36 were identified with Ki values of 2.6 and 1.8 nM, respectively. These two antagonists are also poten...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Sturino CF,Lachance N,Boyd M,Berthelette C,Labelle M,Li L,Roy B,Scheigetz J,Tsou N,Brideau C,Cauchon E,Carriere MC,Denis D,Greig G,Kargman S,Lamontagne S,Mathieu MC,Sawyer N,Slipetz D,O'Neill G,Wang Z,Zamboni R

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  • Design and synthesis of carbamate and thiocarbamate derivatives and their inhibitory activities of NO production in LPS activated macrophages.

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Jin GH,Lee HJ,Gim HJ,Ryu JH,Jeon R

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zvarec O,Polyak SW,Tieu W,Kuan K,Dai H,Pedersen DS,Morona R,Zhang L,Booker GW,Abell AD

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Rosen TJ,Coffman KJ,McLean S,Crawford RT,Bryce DK,Gohda Y,Tsuchiya M,Nagahisa A,Nakane M,Lowe JA 3rd

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Gududuru V,Zeng K,Tsukahara R,Makarova N,Fujiwara Y,Pigg KR,Baker DL,Tigyi G,Miller DD

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  • DNA triplex structures are stabilized by the incorporation of 3'-endo blocked pyrimidine nucleosides in the Hoogsteen strand.

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Savy P,Benhida R,Fourrey JL,Maurisse R,Sun JS

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Shi J,Xiao Z,Ihnat MA,Kamat C,Pandit B,Hu Z,Li PK

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Takadoi M,Yamaguchi K,Terashima S

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Gandolfi R,Marinelli F,Ragg E,Romano D,Molinari F

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    journal_title:Bioorganic & medicinal chemistry letters

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    authors: Kim T,Choi HJ,Eom SH,Lee J,Kim TH

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Gaudette F,Raeppel S,Nguyen H,Beaulieu N,Beaulieu C,Dupont I,Macleod AR,Besterman JM,Vaisburg A

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    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yang W,Mou T,Guo W,Jing H,Peng C,Zhang X,Ma Y,Liu B

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