当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY期刊下所有文献 > Functionalized 6-(piperidin-1-yl)-8,9-diphenyl purines as inverse agonists of the CB1 receptor - SAR efforts towards selectivity and peripheralization.

Functionalized 6-(piperidin-1-yl)-8,9-diphenyl purines as inverse agonists of the CB1 receptor - SAR efforts towards selectivity and peripheralization.

Abstract：

:Antagonists of type 1 cannabinoid receptors (CB1) may be useful in treating diabetes, hepatic disorders, and fibrosis. Otenabant (1) is a potent and selective CB1 inverse agonist that was under investigation as an anti-obesity agent, but its development was halted once adverse effects associated with another marketed inverse agonist rimonabant (2) became known. Non-tissue selective antagonists of CB1 that have high levels of brain penetration produce adverse effects in a small subset of patients including anxiety, depression and suicidal ideation. Currently, efforts are underway to produce compounds that have limited brain penetration. In this report, novel analogs of 1 are explored to develop and test strategies for peripheralization. The piperidine of 1 is studied as a linker, which is functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a connector in the form of an amine, amide, sulfonamide, sulfamide, carbamate, oxime, amidine, or guanidine. We also report more polar replacements for the 4-chlorophenyl group in the 9-position of the purine core, which improve calculated physical properties of the molecules. These studies resulted in compounds such as 75 that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. SAR studies revealed ways to adjust physical properties to limit brain exposure.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Amato G,Wiethe R,Manke A,Vasukuttan V,Snyder R,Runyon S,Maitra R

doi

10.1016/j.bmc.2019.07.002

subject

Has Abstract

pub_date

2019-08-15 00:00:00

pages

3632-3649

issue

16

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(19)30643-1

journal_volume

27

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY文献大全
  • Cytotoxic 3,6-bis((imidazolidinone)imino)acridines: synthesis, DNA binding and molecular modeling.

    abstract：:New acridine derivatives bearing two symmetrical imidazolidinone rings, 3,6-bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides 6a-6e (alkyl=ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl), have been prepared and their interactions with calf thymus DNA and selected cell lines were studied. The DNA-bind...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2011.01.012

    authors： Janovec L,Kožurková M,Sabolová D,Ungvarský J,Paulíková H,Plšíková J,Vantová Z,Imrich J

    更新日期：2011-03-01 00:00:00

  • Investigating the activity of 2-substituted alkyl-6-(2,5-dioxopyrrolidin-1-yl)hexanoates as skin penetration enhancers.

    abstract：:Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. We generated two series of esters by multi-step synthesis with substituted 6-aminohexanoic acid as potential transdermal penetration enhancers by multi-step synthesis. Th...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2010.10.025

    authors： Brychtova K,Opatrilova R,Raich I,Kalinowski DS,Dvorakova L,Placek L,Csollei J,Richardson DR,Jampilek J

    更新日期：2010-12-15 00:00:00

  • Synthesis and in vitro evaluation of radioiodinated indolequinones targeting NAD(P)H: quinone oxidoreductase 1 for internal radiation therapy.

    abstract：NAD(P)H:quinone oxidoreductase 1 (NQO1) is an obligate two-electron reductase and is highly expressed in many human solid cancers. Because NQO1 can be induced immediately after exposure to ionizing radiation, we aimed to develop an NQO1-targeted radiolabeled agent to establish a novel internal radiation therapy that am...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2014.09.006

    authors： Sasaki J,Sano K,Hagimori M,Yoshikawa M,Maeda M,Mukai T

    更新日期：2014-11-01 00:00:00

  • Inhibition of the Ser-Thr phosphatases PP1 and PP2A by naturally occurring toxins.

    abstract：:The okadaic acid class of naturally occurring toxins is a structurally diverse group of molecules that inhibit the protein phosphatases PP1 and PP2A. Studies providing information about the mode of binding between the toxins and the phosphatases contribute to an overall understanding of the signal transduction pathway...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1016/s0968-0896(97)00146-6

    authors： Sheppeck JE 2nd,Gauss CM,Chamberlin AR

    更新日期：1997-09-01 00:00:00

  • QSAR of 1,4-benzoxazin-3-one antimicrobials and their drug design perspectives.

    abstract：:Synthetic derivatives of 1,4-benzoxazin-3-ones have been shown to possess promising antimicrobial activity, whereas their natural counterparts were found lacking in this respect. In this work, quantitative structure-activity relationships (QSAR) of natural and synthetic 1,4-benzoxazin-3-ones as antimicrobials were est...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2018.11.016

    authors： de Bruijn WJC,Hageman JA,Araya-Cloutier C,Gruppen H,Vincken JP

    更新日期：2018-12-15 00:00:00

  • Synthesis and biological evaluation of pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane derivatives as potential therapeutic agents in Parkinson's disease.

    abstract：:In previous studies, the polycyclic cage amine 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane (NGP1-01) and a number of its derivatives showed positive effects in neuroprotection studies with MPTP, in vivo. In view of these findings, we examined these compounds for their effects on [(3)H]dopamin...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2003.12.045

    authors： Geldenhuys WJ,Malan SF,Murugesan T,Van der Schyf CJ,Bloomquist JR

    更新日期：2004-04-01 00:00:00

  • Tryptophan-based fluorophores for studying protein conformational changes.

    abstract：:With the continuing interest in deciphering the interplay between protein function and conformational changes, small fluorescence probes will be especially useful for tracking changes in the crowded protein interior space. Presently, we describe the potential utility of six unnatural amino acid fluorescence donors str...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2014.09.015

    authors： Talukder P,Chen S,Liu CT,Baldwin EA,Benkovic SJ,Hecht SM

    更新日期：2014-11-01 00:00:00

  • Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling.

    abstract：:We disclose herein our efforts aimed at discovery of selective PARP-1 and PARP-2 inhibitors. We have recently discovered several novel classes of quinazolinones, quinazolidinones, and quinoxalines as potent PARP-1 inhibitors, which may represent attractive therapeutic candidates. In PARP enzyme assays using recombinan...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2005.09.061

    authors： Ishida J,Yamamoto H,Kido Y,Kamijo K,Murano K,Miyake H,Ohkubo M,Kinoshita T,Warizaya M,Iwashita A,Mihara K,Matsuoka N,Hattori K

    更新日期：2006-03-01 00:00:00

  • 1,2,4-triazolo[1,5-a]quinoxaline derivatives and their simplified analogues as adenosine A₃ receptor antagonists. Synthesis, structure-affinity relationships and molecular modeling studies.

    abstract：:The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2-15). This study produced some interesting compoun...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2014.11.033

    authors： Catarzi D,Varano F,Poli D,Squarcialupi L,Betti M,Trincavelli L,Martini C,Dal Ben D,Thomas A,Volpini R,Colotta V

    更新日期：2015-01-01 00:00:00

  • Sequential and parallel dual labeling of nanoparticles using click chemistry.

    abstract：:Bioorthogonal 'click' reactions have recently emerged as promising tools for chemistry and biological applications. By using a combination of two different 'click' reactions, 'double-click' strategies have been developed to attach multiple labels onto biomacromolecules. These strategies require multi-step modification...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2014.07.015

    authors： Zong H,Goonewardena SN,Chang HN,Otis JB,Baker JR Jr

    更新日期：2014-11-01 00:00:00

  • A CoMSIA study on the adenosine kinase inhibition of pyrrolo[2,3-d]pyrimidine nucleoside analogues.

    abstract：:The structural requirements of pyrrolo[2,3-d]pyrimidine nucleoside (PPN) analogues as adenosine kinase (AK) inhibitors were in silico studied by using CoMSIA method. All models were trained with 32 compounds, after which they were evaluated for predictive ability with additional 5 compounds. Quantitative information o...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.03.027

    authors： Caballero J,Fernández M,González-Nilo FD

    更新日期：2008-05-01 00:00:00

  • An LP1 analogue, selective MOR agonist with a peculiar pharmacological profile, used to scrutiny the ligand binding domain.

    abstract：:The hypothesis that central analgesia with reduced side effects is obtainable by occupying an 'allosteric' site in the MOR ligand binding domain requires the development of new ligands with peculiar pharmacological profile to be used as tools. New benzomorphan derivatives, analogues of LP1, a multitarget MOR agonist/D...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2016.08.057

    authors： Ronsisvalle S,Aricò G,Panarello F,Spadaro A,Pasquinucci L,Pappalardo MS,Parenti C,Ronsisvalle N

    更新日期：2016-11-01 00:00:00

  • A quencher-free molecular beacon design based on pyrene excimer fluorescence using pyrene-labeled UNA (unlocked nucleic acid).

    abstract：:A quencher-free molecular beacon capable of generating pyrene excimer fluorescence has been constructed using strategically positioned pyrene-UNA monomers. Hybridization of a fully complementary RNA target was accompanied by a pyrene excimer emission increase of more than 900%, and detection of RNA in living cells was...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.04.062

    authors： Karlsen KK,Okholm A,Kjems J,Wengel J

    更新日期：2013-10-15 00:00:00

  • Synthesis and anti-inflammatory activity of isoquebecol.

    abstract：:We report here the synthesis of isoquebecol, an unprecedented constitutional isomer of quebecol, a polyphenolic compound discovered in maple syrup. The methodology used to prepare isoquebecol involves, as key steps, the formation of a dibromoalkene from an α-ketoester precursor, followed by a double Suzuki-Miyaura rea...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2017.01.050

    authors： Cardinal S,Paquet-Côté PA,Azelmat J,Bouchard C,Grenier D,Voyer N

    更新日期：2017-04-01 00:00:00

  • Computer-aided discovery of aminopyridines as novel JAK2 inhibitors.

    abstract：:The Janus kinase 2 (JAK2)-mediated signaling pathway plays an important role in controlling cell survival, proliferation, and differentiation. In recent years, genetic, biological, and physiological evidence has established JAK2 inhibitors as effective chemotherapeutic agents for the treatment of many different cancer...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2015.01.016

    authors： Zhao C,Yang SH,Khadka DB,Jin Y,Lee KT,Cho WJ

    更新日期：2015-03-01 00:00:00

  • Dolastatin 11 conformations, analogues and pharmacophore.

    abstract：:Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2005.04.040

    authors： Ali MA,Bates RB,Crane ZD,Dicus CW,Gramme MR,Hamel E,Marcischak J,Martinez DS,McClure KJ,Nakkiew P,Pettit GR,Stessman CC,Sufi BA,Yarick GV

    更新日期：2005-07-01 00:00:00

  • The hemA gene encoding glutamyl-tRNA reductase from the archaeon Methanobacterium thermoautotrophicum strain Marburg.

    abstract：:In archaea the first general tetrapyrrole precursor 5-aminolevulinic acid (ALA) is formed via the tRNA-dependent five-carbon pathway from glutamate. We have cloned the hemA gene encoding the central enzyme of the pathway glutamyl-tRNA reductase from the methanogenic archaeon Methanobacterium thermoautotrophicum by com...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/0968-0896(96)00098-3

    authors： Hungerer C,Weiss DS,Thauer RK,Jahn D

    更新日期：1996-07-01 00:00:00

  • Antifungal polyketide derivatives from the endophytic fungus Aplosporella javeedii.

    abstract：:Six new polyketides aplojaveediins A-F (1-6) were isolated from the endophytic fungus Aplosporella javeedii associated with the host plant Orychophragmus violaceus (Brassicaceae). The structures of the new metabolites were elucidated by analysis of their NMR and MS data. Compound 1 exhibited antifungal activity agains...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2020.115456

    authors： Gao Y,Wang L,Kalscheuer R,Liu Z,Proksch P

    更新日期：2020-05-15 00:00:00

  • Synthesis and evaluation of [14C]-labelled and fluorescent-tagged paclitaxel derivatives as new biological probes.

    abstract：:Our present report deals with the preparation of hitherto unreported 7-([carbonyl-14C]-acetyl)paclitaxel 4 and two new bioactive 7-substituted fluorescent taxoids (FITC 9 and rhodamine 11), as well as evaluation towards their applications as biological probes. The results in this report demonstrate that (a) the new pa...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(98)00158-8

    authors： Rao CS,Chu JJ,Liu RS,Lai YK

    更新日期：1998-11-01 00:00:00

  • Preparation and antioxidant activity of alpha-pyridoin and its derivatives.

    abstract：:Focusing on alpha-pyridoin (1, 1,2-di(2-pyridyl)-1,2-ethenediol) as the lead compound of the novel antioxidative enediol, we synthesized 5,5'- or 6,6'-bis-substituted derivatives of 1 from disubstituted pyridines. The antioxidant activity of 1 and its synthetic derivatives 2-7 was evaluated by DPPH (1,1-diphenyl-2-pic...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2005.07.065

    authors： Hatanaka M,Takahashi K,Nakamura S,Mashino T

    更新日期：2005-12-15 00:00:00

  • Synthesis of 16-(bromoalkyl)-estradiols having inhibitory effect on human placental estradiol 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD type 1).

    abstract：:The activity of 17 beta-HSD type 1, the enzyme that converts estrone into its more potent metabolite estradiol, has been demonstrated in all classical steroidogenic tissues and almost all peripheral tissues from both rat and human. Since 17 beta-HSD is one of the most important enzymes involved in active steroid hormo...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/0968-0896(95)00041-e

    authors： Tremblay MR,Auger S,Poirier D

    更新日期：1995-05-01 00:00:00

  • Model studies for isolation of G-quadruplex-forming DNA sequences through a pull-down strategy with macrocyclic polyoxazole.

    abstract：:G-quadruplexes (G4s) are non-B DNA structures present in guanine-rich regions of gene regulatory areas, promoters and CpG islands, but their occurrence and functions remain incompletely understood. Thus, methodology to identify G4 sequences is needed. Here, we describe the synthesis of a novel cyclic hepta-oxazole com...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2019.02.056

    authors： Iida K,Tsushima Y,Ma Y,Sedghi Masoud S,Sakuma M,Yokoyama T,Yoshida W,Ikebukuro K,Nagasawa K

    更新日期：2019-04-15 00:00:00

  • Synthesis of chlorogenic acid derivatives with promising antifungal activity.

    abstract：:Derivatives of chlorogenic acid or its analogues were synthesized by coupling protected chlorogenic acid or its analogues with p-octyloxyaniline and selected amino acids. Most of the compounds exhibited significant potency against Cryptococcus neoformans and Candida species with low toxicity to brine shrimps. The 4,5-...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2007.07.038

    authors： Ma CM,Kully M,Khan JK,Hattori M,Daneshtalab M

    更新日期：2007-11-01 00:00:00

  • DNA sequence-specific recognition of peptides incorporating the HPRK and polyamide motifs.

    abstract：:Three peptide amides, HPRK(Py)(4)HPRK-NH(2) (PyH-12), HPRK(Py)(3)HPRK-NH(2) (PyH-11) and HPRK(Py)(2)HPRK-NH(2) (PyH-10), incorporating two HPRK motifs and various 4-amino-1-methylpyrrole-2-carboxylic acid residues (Py) were synthesized by solid-phase peptide methodology. The binding of these three peptides to a 5'-32P...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2003.10.049

    authors： Chang JC,Yang CH,Chou PY,Yang WH,Chou IC,Lu CT,Lin PH,Hou RC,Jeng KC,Cheng CC,Sheh L

    更新日期：2004-01-02 00:00:00

  • Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors.

    abstract：:A series of non-covalent piperidine-containing peptidyl derivatives with various substituents at side chains of different residues were designed, synthesized and evaluated as proteasome inhibitors. After proteasome inhibitory evaluations of all the synthesized target compounds, selected ones were tested for their anti...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2020.115867

    authors： Zhao Y,Xu L,Zhang J,Zhang M,Lu J,He R,Xi J,Zhuang R,Li J,Zhou Y

    更新日期：2021-01-01 00:00:00

  • Synthesis and preliminary in vivo evaluation of new [18F]fluoro-inositols as Positron Emission Tomography radiotracers.

    abstract：:This study describes the synthesis and radiosynthesis of eight new [18F]fluoro-inositol-based radiotracers in myo- and scyllo-inositol configuration. These radiotracers are equipped with a propyl linker bearing fluorine-18. This fluorinated arm is either on a hydroxyl group, i.e. O-alkylated inositols, or on the cyclo...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2017.08.035

    authors： Collet C,Schmitt S,Maskali F,Clément A,Chrétien F,Karcher G,Marie PY,Poussier S,Lamandé-Langle S

    更新日期：2017-10-15 00:00:00

  • General synthesis and biological evaluation of alpha-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-alpha-C-glycosides).

    abstract：:A general synthesis of alpha-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-alpha-C-glycosides) by ring-opening reactions of an aziridine with various heteroatomic nucleophiles, including thiol, amine, alcohol, carboxylate and phosphate, is described. The nine-step reaction sequence proceeded in an overal...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2004.12.043

    authors： Goujon JY,Gueyrard D,Compain P,Martin OR,Ikeda K,Kato A,Asano N

    更新日期：2005-03-15 00:00:00

  • Enzymatic resolution of racemates with a 'remote' stereogenic center as an efficient tool in drug, flavor and vitamin synthesis.

    abstract：:The enantioselective recognition of 'remote' stereogenic centers represents a scientific task in organic chemistry being also of current interest in the pharmaceutical industry. This is due to a range of pharmaceutically relevant molecules or intermediates thereof bearing a stereogenic center, which is separated from ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1016/j.bmc.2014.06.024

    authors： Alfaro Blasco M,Gröger H

    更新日期：2014-10-15 00:00:00

  • Novel BACE1 inhibitors with a non-acidic heterocycle at the P1' position.

    abstract：:We have reported potent peptidic and non-peptidic BACE1 inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. However, our potent inhibitors possess a tetrazole ring at the P1' position. It is desirable that central nervous system (CNS) drugs do not possess an acidic moiety. In ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.08.016

    authors： Suzuki K,Hamada Y,Nguyen JT,Kiso Y

    更新日期：2013-11-01 00:00:00

  • Design, modelling, synthesis and biological evaluation of peptidomimetic phosphinates as inhibitors of matrix metalloproteinases MMP-2 and MMP-8.

    abstract：:Three novel peptidomimetic phosphinate inhibitors have been synthesized and evaluated as inhibitors of matrix metalloproteinases MMP-2 and MMP-8. Their IC50 values are in the micromolar range, and one of them showed to be the most effective inhibitor of MMP-2. The differences in binding affinities for MMP-2 and MMP-8 ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2005.04.079

    authors： Bianchini G,Aschi M,Cavicchio G,Crucianelli M,Preziuso S,Gallina C,Nastari A,Gavuzzo E,Mazza F

    更新日期：2005-08-01 00:00:00