Evaluation of 1,2,5-thiadiazoles as modulators of M₁/M₅ muscarinic receptor subtypes.


:Studies have demonstrated the presence of allosteric binding sites on each of the muscarinic acetylcholine receptor (mAChR) subtypes. Since most drugs targeting muscarinic receptors bind to the highly conserved orthosteric binding site, they fail to achieve appreciable subtype selectivity. Targeting non-conserved allosteric sites may provide a new way of enhancing selectivity for individual subtypes of muscarinic receptor. Tetra(ethyleneglycol)(3-methoxy-1,2,5-thiadiazol-4-yl)[3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether, CDD-0304 (10), was found to be a M₁/₂/₄ selective muscarinic agonist and might prove useful in treating the symptoms associated with schizophrenia (J. Med. Chem.2003, 46, 4273). It was hypothesized that the observed subtype selectivity demonstrated by 10 may be due to its ability to function as a bitopic ligand (J. Med. Chem.2006, 49, 7518). To further investigate this possibility, a novel series of compounds was synthesized using a 1,2,5-thiadiazole moiety along with varying lengths of a polyethylene glycol linker and terminal groups, for evaluation as potential allosteric modulators of muscarinic receptors. Preliminary biological studies were performed using carbachol to stimulate M₁ and M₅ receptors. No significant agonist activity was observed at either M₁ or M₅ receptors for any of the compounds. Compound 18, 2-(4-methoxy-1,2,5-thiadiazol-3-yloxy)-N,N-dimethylethanamine fumarate (CDD-0361F) was found to block the effects of carbachol at M5 muscarinic receptors.


Bioorg Med Chem


Maheshwari A,Rao PS,Messer WS Jr




Has Abstract


2014-03-15 00:00:00














  • Carbonic anhydrases as targets for medicinal chemistry.

    abstract::Carbonic anhydrases (CAs, EC are zinc enzymes acting as efficient catalysts for the reversible hydration of carbon dioxide to bicarbonate. 16 different alpha-CA isoforms were isolated in mammals, where they play crucial physiological roles. Some of them are cytosolic (CA I, CA II, CA III, CA VII, CA XIII), ot...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章,评审


    authors: Supuran CT,Scozzafava A

    更新日期:2007-07-01 00:00:00

  • Structure-activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template.

    abstract::In an effort to design inhibitors of human glutaminyl cyclase (QC), we have synthesized a library of N-aryl N-(5-methyl-1H-imidazol-1-yl)propyl thioureas and investigated the contribution of the aryl region of these compounds to their structure-activity relationships as cyclase inhibitors. Our design was guided by the...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Tran PT,Hoang VH,Thorat SA,Kim SE,Ann J,Chang YJ,Nam DW,Song H,Mook-Jung I,Lee J,Lee J

    更新日期:2013-07-01 00:00:00

  • 5-Nitro-2-furfuriliden derivatives as potential anti-Trypanosoma cruzi agents: design, synthesis, bioactivity evaluation, cytotoxicity and exploratory data analysis.

    abstract::The anti-Trypanosoma cruzi activity of 5-nitro-2-furfuriliden derivatives as well as the cytotoxicity of these compounds on J774 macrophages cell line and FN1 human fibroblast cells were investigated in this study. The most active compounds of series I and II were 4-butyl-[N'-(5-nitrofuran-2-yl) methylene] benzidrazid...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Palace-Berl F,Jorge SD,Pasqualoto KF,Ferreira AK,Maria DA,Zorzi RR,de Sá Bortolozzo L,Lindoso JÂ,Tavares LC

    更新日期:2013-09-01 00:00:00

  • Astersedifolioside A-C, three new oleane-type saponins with antiproliferative activity.

    abstract::A phytochemical analysis of Aster sedifolius has led to the isolation of three novel triterpenoid saponins, based on an oleane-type skeleton and named astersedifolioside A (1), B (2) and C (3). On the basis of chemical, and 2D NMR and mass spectrometry data, the structures of the new compounds were elucidated as 3-O-[...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Corea G,Iorizzi M,Lanzotti V,Cammareri M,Conicella C,Laezza C,Bifulco M

    更新日期:2004-09-15 00:00:00

  • Discovery and preclinical development of AR453588 as an anti-diabetic glucokinase activator.

    abstract::Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high levels of glucose. Flux through GK is also responsible for reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identify...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Hinklin RJ,Baer BR,Boyd SA,Chicarelli MD,Condroski KR,DeWolf WE Jr,Fischer J,Frank M,Hingorani GP,Lee PA,Neitzel NA,Pratt SA,Singh A,Sullivan FX,Turner T,Voegtli WC,Wallace EM,Williams L,Aicher TD

    更新日期:2020-01-01 00:00:00

  • Identification of an achiral analogue of J-113397 as potent nociceptin/orphanin FQ receptor antagonist.

    abstract::To date, J-113397 represents the most potent and selective non peptide NOP receptor antagonist widely used in pharmacological studies. However, the synthesis, purification, and enantiomer separation of this molecule, which contains two chiral centers, is rather difficult and low-yielding. Here, we synthesized and test...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Trapella C,Guerrini R,Piccagli L,Calo' G,Carra' G,Spagnolo B,Rubini S,Fanton G,Hebbes C,McDonald J,Lambert DG,Regoli D,Salvadori S

    更新日期:2006-02-01 00:00:00

  • Structural insights into the hot spot amino acid residues of mushroom tyrosinase for the bindings of thujaplicins.

    abstract::Tyrosinase inhibitors are important agents for cosmetic products. We examined here the inhibitory effects of three isomers of thujaplicins (α, β and γ) on mushroom tyrosinase and analyzed their binding modes using a homology model from the crystal structure of Streptomyces castaneoglobisporus tyrosinase (PDB ID: 1wx2)...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Takahashi S,Kamiya T,Saeki K,Nezu T,Takeuchi S,Takasawa R,Sunaga S,Yoshimori A,Ebizuka S,Abe T,Tanuma S

    更新日期:2010-11-15 00:00:00

  • Synthesis and biological evaluation of novel irreversible serine protease inhibitors using amino acid based sulfonyl fluorides as an electrophilic trap.

    abstract::We have designed and synthesized novel irreversible serine protease inhibitors containing aliphatic sulfonyl fluorides as an electrophilic trap. These substituted taurine sulfonyl fluorides derived from taurine or protected amino acids were conveniently synthesized from β-aminoethanesulfonyl chlorides using KF/18-crow...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Brouwer AJ,Ceylan T,Jonker AM,van der Linden T,Liskamp RM

    更新日期:2011-04-01 00:00:00

  • A novel fluorescent probe based on naphthalimide for imaging nitroreductase (NTR) in bacteria and cells.

    abstract::A nitroreductase (NTR) responsive fluorescent probe, Na-NO2, comprising p-nitrobenzyl as the unique recognition group and 1,8-naphthalimide as fluorophore, was synthesized. Na-NO2 showed remarkable fluorescence "turn-on" signal in the presence of NTR under DMSO/H2O (1:19, v/v) buffered with PBS (pH = 7) solution in th...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Zhang Z,Lv T,Tao B,Wen Z,Xu Y,Li H,Liu F,Sun S

    更新日期:2020-02-01 00:00:00

  • Metallocene-based antimalarials: an exploration into the influence of the ferrocenyl moiety on in vitro antimalarial activity in chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum.

    abstract::To establish the role of the ferrocenyl moiety in the antiplasmodial activity of ferroquine, compounds in which this moiety is replaced by the corresponding ruthenium-based moieties were synthesized and evaluated. In both the sensitive (D10) and resistant (K1) strains of Plasmodium falciparum, ruthenoquine analogues s...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Blackie MA,Beagley P,Croft SL,Kendrick H,Moss JR,Chibale K

    更新日期:2007-10-15 00:00:00

  • Physicochemical and biological study of selected hydrophobic polyethylenimine-based polycationic liposomes and their complexes with DNA.

    abstract::Non-viral gene therapy is based on the development of efficient and safe gene carrier systems able to transfer DNA into cells. Polyethylenimine (PEI), the most promising non-viral vector, with its high cationic-charge-density potential is able (1) to compact DNA in complexes (polyplexes) smaller than those formed by l...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Masotti A,Moretti F,Mancini F,Russo G,Di Lauro N,Checchia P,Marianecci C,Carafa M,Santucci E,Ortaggi G

    更新日期:2007-02-01 00:00:00

  • Hypericins and thioredoxin reductase: Biochemical and docking studies disclose the molecular basis for effective inhibition by naphthodianthrones.

    abstract::Cytosolic (TrxR1) and mitochondrial (TrxR2) thioredoxin reductases experience pronounced concentration- and time-dependent inhibition when incubated with the two naphthodianthrones hypericin and pseudohypericin. Pseudohypericin turned out to be a quite strong inhibitor of TrxR1 (IC(50)=4.40μM) being far more effective...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Sorrentino F,Karioti A,Gratteri P,Rigobello MP,Scutari G,Messori L,Bindoli A,Chioccioli M,Gabbiani C,Bergonzi MC,Bilia AR

    更新日期:2011-01-01 00:00:00

  • Discovery of 1H-benzo[d][1,2,3]triazol-1-yl 3,4,5-trimethoxybenzoate as a potential antiproliferative agent by inhibiting histone deacetylase.

    abstract::Twenty-one benzotriazoles (3-16 and 18-24) were synthesized and half of them (5, 8-16, 20, and 21) were reported for the first time. Their antiproliferative activities against three human cancer cells were assayed. It revealed that 1H-benzo[d][1,2,3]triazol-1-yl 3,4,5-trimethoxybenzoate (9) showed considerable activit...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Fu J,Yang Y,Zhang XW,Mao WJ,Zhang ZM,Zhu HL

    更新日期:2010-12-15 00:00:00

  • Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity.

    abstract::Compounds that bind at the colchicine site of tubulin have drawn considerable attention with studies indicating that these agents suppress microtubule dynamics and inhibit tubulin polymerization. Data for 18 polysubstituted pyrrole compounds are reported, including antiproliferative activity against human MDA-MB-435 c...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Tripathi A,Fornabaio M,Kellogg GE,Gupton JT,Gewirtz DA,Yeudall WA,Vega NE,Mooberry SL

    更新日期:2008-03-01 00:00:00

  • Mechanism of influence of phosphorylation on serine 124 on a decrease of catalytic activity of human thymidylate synthase.

    abstract::Regulation by phosphorylation is a well-established mechanism for controlling biological activity of proteins. Recently, phosphorylation of serine 124 in human thymidylate synthase (hTS) has been shown to lower the catalytic activity of the enzyme. To clarify a possible mechanism of the observed influence, molecular d...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Jarmuła A,Fraczyk T,Cieplak P,Rode W

    更新日期:2010-05-15 00:00:00

  • Biology-oriented synthesis of benzopyrano[3,4-c]pyrrolidines.

    abstract::A natural product inspired synthesis of 6,6,5-tricyclic compounds via a silver(I)-catalyzed formal 1,3-dipolar cycloaddition of coumarins with α-iminoesters was developed. The reaction proceeds in a stepwise reaction course under formation of the trans-substituted diastereomer with respect to the 1,3-dipole and shows ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Potowski M,Golz C,Strohmann C,Antonchick AP,Waldmann H

    更新日期:2015-06-15 00:00:00

  • Anti-tumor activity of the farnesyl-protein transferase inhibitors arteminolides, isolated from Artemisa.

    abstract::Members of the Artemisia genus are important medicinal plants found throughout the world. Arteminolides A-D (1-4), isolated from the aerial parts of Artemisia, have an inhibitory activity on farnesyl-protein transferase (FPTase; EC in in vitro assay. This study was carried out with the purpose of validating ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Lee SH,Lee MY,Kang HM,Han DC,Son KH,Yang DC,Sung ND,Lee CW,Kim HM,Kwon BM

    更新日期:2003-10-15 00:00:00

  • Effective syntheses of 2',4'-BNANC monomers bearing adenine, guanine, thymine, and 5-methylcytosine, and the properties of oligonucleotides fully modified with 2',4'-BNANC.

    abstract::We efficiently synthesized 2'-O,4'-C-aminomethylene-bridged nucleic acid (2',4'-BNANC) monomers bearing the four nucleobases, guanine, adenine, thymine, and 5-methylcytosine and incorporated these monomers into oligonucleotides. Initially, we carried out the transglycosylation reaction on several 2'-O-substituted 5-me...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Fujisaka A,Hari Y,Takuma H,Rahman SMA,Yoshikawa H,Pang J,Imanishi T,Obika S

    更新日期:2019-04-15 00:00:00

  • A new motif for inhibitors of geranylgeranyl diphosphate synthase.

    abstract::The enzyme geranylgeranyl diphosphate synthase (GGDPS) is believed to receive the substrate farnesyl diphosphate through one lipophilic channel and release the product geranylgeranyl diphosphate through another. Bisphosphonates with two isoprenoid chains positioned on the α-carbon have proven to be effective inhibitor...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Foust BJ,Allen C,Holstein SA,Wiemer DF

    更新日期:2016-08-15 00:00:00

  • Discovery of a new type of scaffold for the creation of novel tyrosinase inhibitors.

    abstract::Tyrosinase is known as the key enzyme for melanin biosynthesis, which is effective in preventing skin injury by ultra violet (UV). In past decades, tyrosinase has been well studied in the field of cosmetics, medicine, agriculture and environmental sciences, and a lot of tyrosinase inhibitors have been developed for th...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Oyama T,Takahashi S,Yoshimori A,Yamamoto T,Sato A,Kamiya T,Abe H,Abe T,Tanuma SI

    更新日期:2016-09-15 00:00:00

  • Radical scavenging and cytochrome P450 3A4 inhibitory activity of bergaptol and geranylcoumarin from grapefruit.

    abstract::Grapefruit juice has been shown to increase the oral bioavailability of several clinically important drugs by inhibiting first pass metabolism. Several compounds in grapefruit juice have shown different biological activities. Unique among them are furocoumarins with potent inhibitory activity against cytochrome P450 e...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Girennavar B,Jayaprakasha GK,Jadegoud Y,Nagana Gowda GA,Patil BS

    更新日期:2007-06-01 00:00:00

  • Protective effect of ε-viniferin on β-amyloid peptide aggregation investigated by electrospray ionization mass spectrometry.

    abstract::Abnormal β-amyloid peptide accumulation and aggregation is considered to be responsible for the formation and cerebral deposition of senile plaques in the brains of patients with Alzheimer's disease (AD). Inhibition of the formation of β-amyloid (Aβ) fibrils would be an attractive therapeutic target for the treatment ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Richard T,Poupard P,Nassra M,Papastamoulis Y,Iglésias ML,Krisa S,Waffo-Teguo P,Mérillon JM,Monti JP

    更新日期:2011-05-15 00:00:00

  • Cell-based biological evaluations of 5-(3-bromo-4-phenethoxybenzylidene)thiazolidine-2,4-dione as promising wound healing agent.

    abstract::Recent studies have focused on prostaglandin E₂ (PGE₂) because PGE₂ regulates vertebrate hematopoietic stem cell induction and engraftment. PGE₂ acts through EP2 and EP4 receptors to mediate regeneration and hematopoietic stem cell (HSC) development via the Wnt signaling pathway. Previously we reported that inhibitors...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Piao YL,Ram Song A,Cho H

    更新日期:2015-05-01 00:00:00

  • An extended study of dimeric phenyl tropanes.

    abstract::A series of dimeric phenyl tropanes consisting of two molecules of 4-chloro, 4-iodo or 4-(3-thiopheno)-phenyl tropane tethered together at the carboxylic acid moiety by a diamine or diol linker were prepared. The diamines used were a variety of linear, cyclic and aromatic diamines, while the diol tethered compounds we...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Nielsen S,Pedersen CM,Hansen SG,Petersen MD,Sinning S,Wiborg O,Jensen HH,Bols M

    更新日期:2009-07-15 00:00:00

  • Synthesis, biological assays and QSAR studies of N-(9-benzyl-2-phenyl-8-azapurin-6-yl)-amides as ligands for A1 adenosine receptors.

    abstract::2-Phenyl-9-benzyl-8-azapurines, bearing at the 6 position an amido group interposed between the 8-azapurine moiety and an alkyl or a substituted phenyl group, have been synthesised and assayed as ligands for adenosine receptors. All the compounds show high affinity for the A(1) adenosine receptor, and many of them als...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Giorgi I,Leonardi M,Pietra D,Biagi G,Borghini A,Massarelli I,Ciampi O,Bianucci AM

    更新日期:2009-03-01 00:00:00

  • Synthesis of novel 7-oxo and 7-hydroxy trifluoroallocolchicinoids with cytotoxic effect.

    abstract::The synthesis of 7-oxo and 7-hydroxy trifluoroallocolchicinoids was achieved through the intramolecular cyclization of o-phenyl-β-phenylalanines. The resulting compounds were evaluated for their cytotoxic activity against KB cells and their inhibitory effect towards the polymerization of tubulin. The results yielded s...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Chosson E,Santoro F,Rochais C,Santos JS,Legay R,Thoret S,Cresteil T,Sinicropi MS,Besson T,Dallemagne P

    更新日期:2012-04-15 00:00:00

  • Binding of 2,4-disubstituted morpholines at human D4 dopamine receptors.

    abstract::The synthesis of a series of 2,4-disubstituted morpholines is described and their affinities at human dopamine receptors reported. The orally bioavailable 7-azaindole compound 11 has nanomolar affinity at the hD4 receptor with > 1000-fold selectivity over the hD2 receptor. ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Showell GA,Emms F,Marwood R,O'Connor D,Patel S,Leeson PD

    更新日期:1998-01-01 00:00:00

  • Inhibitory effects of flavonoids isolated from Fragaria ananassa Duch on IgE-mediated degranulation in rat basophilic leukemia RBL-2H3.

    abstract::We isolated the 4 kinds of flavonoids from strawberry 'Nohime' and examined the effect of these flavonoids on the degranulation in RBL-2H3 cells. The flavonoids were found to suppress the degranulation from Ag-stimulated RBL-2H3 cells to different extents. To disclose the inhibitory mechanism of degranulation by flavo...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Itoh T,Ninomiya M,Yasuda M,Koshikawa K,Deyashiki Y,Nozawa Y,Akao Y,Koketsu M

    更新日期:2009-08-01 00:00:00

  • Discovery of INT131: a selective PPARγ modulator that enhances insulin sensitivity.

    abstract::PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile comp...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Taygerly JP,McGee LR,Rubenstein SM,Houze JB,Cushing TD,Li Y,Motani A,Chen JL,Frankmoelle W,Ye G,Learned MR,Jaen J,Miao S,Timmermans PB,Thoolen M,Kearney P,Flygare J,Beckmann H,Weiszmann J,Lindstrom M,Walker N,Li

    更新日期:2013-02-15 00:00:00

  • Synthesis, in vitro and in vivo preliminary evaluation of anti-angiogenic properties of some pyrroloazaflavones.

    abstract::This work investigated the in vitro and in vivo anti-angiogenic activity of some pyrroloazaflavones, exactly 2-phenyl-1H-pyrrolo[2,3-h]quinolin-4(7H)ones, with vinblastine as reference compound. Growth inhibitory activity, migration, and capillary-like structures formation were determined in human umbilical vein endot...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ferlin MG,Conconi MT,Urbani L,Oselladore B,Guidolin D,Di Liddo R,Parnigotto PP

    更新日期:2011-01-01 00:00:00