Novel and potent calcium-sensing receptor antagonists: discovery of (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate (TAK-075) as an orally active bone anabolic agent.


:The calcium-sensing receptor antagonist (CaSR) has been recognized as a promising target of anabolic agents for treating osteoporosis. In the course of developing a new drug candidate for osteoporosis, we found tetrahydropyrazolopyrimidine derivative 1 to be an orally active CaSR antagonist that stimulated transient PTH secretion in rats. However, compound 1 showed poor physical and chemical stability. In order to work out this compound's chemical stability and further understand its in vivo efficacy, we focused on modifying the 2-position of the tetrahydropyrazolopyrimidine. As a result of chemical modification, we discovered (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate 10m (TAK-075), which showed improved solubility, chemical stability, and in vivo efficacy. Furthermore, we describe that evaluating the active metabolite is important during repeated treatment with short-acting CaSR antagonists.


Bioorg Med Chem


Yoshida M,Mori A,Morimoto S,Kotani E,Oka M,Notoya K,Makino H,Ono M,Shirasaki M,Tada N,Fujita H,Ban J,Ikeda Y,Kawamoto T,Goto M,Kimura H,Baba A,Yasuma T




Has Abstract


2011-03-15 00:00:00














  • Synthesis and antimicrobial evaluation of some new substituted purine derivatives.

    abstract::A series of 8,9-disubstituted adenines (4, 5, 8), 6-substituted aminopurines (10-13) and 9-(p-fluorobenzyl/cyclopentyl)-6-substituted aminopurines (16, 17, 19-30) have been prepared and the antimicrobial activities of these compounds against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA, standard and cl...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Tunçbilek M,Ateş-Alagöz Z,Altanlar N,Karayel A,Ozbey S

    更新日期:2009-02-15 00:00:00

  • Synthesis, anticoagulant and PIVKA-II induced by new 4-hydroxycoumarin derivatives.

    abstract::The action of the coumarin-type drugs and related compounds is reviewed to their VKOR antagonistic effects. In our study, twenty 3-pyridinyl, pyrimidinyl and pyrazolyl-4-hydroxycoumarin derivatives were synthesized. A comparative in vivo (CT, PT determination) and in vitro (measurement of PIVKA-II levels) anticoagulan...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Abdelhafez OM,Amin KM,Batran RZ,Maher TJ,Nada SA,Sethumadhavan S

    更新日期:2010-05-15 00:00:00

  • Inhibition studies of new ureido-substituted sulfonamides incorporating a GABA moiety against human carbonic anhydrase isoforms I-XIV.

    abstract::Reaction of γ-Boc-GABA, prepared by protecting the γ-amino moiety of the amino butyric acid with the tert-butyloxycarbonyl (Boc) protecting group, with 4-methyl/ethyl benzenesulfonamide, followed by removal of the Boc protecting group in 3 M HCl afforded the corresponding hydrochlorides, which were further derivatized...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ceruso M,Antel S,Vullo D,Scozzafava A,Supuran CT

    更新日期:2014-12-15 00:00:00

  • Novel tricyclic Delta(2)-isoxazoline and 3-oxo-2-methyl-isoxazolidine derivatives: synthesis and binding affinity at neuronal nicotinic acetylcholine receptor subtypes.

    abstract::A group of novel tricyclic Delta(2)-isoxazolines (4b, 5b, 7a-b, and 8a-b) and 3-oxo-isoxazolidines (6a-b and 9a-b), structurally related to cytisine or norferruginine, was prepared through 1,3-dipolar cycloadditions involving suitable olefins and bromonitrile oxide. The target compounds were assayed at alpha4beta2 and...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Dallanoce C,Frigerio F,Martelli G,Grazioso G,Matera C,Pomè DY,Pucci L,Clementi F,Gotti C,De Amici M

    更新日期:2010-06-15 00:00:00

  • CYP19 (aromatase): exploring the scaffold flexibility for novel selective inhibitors.

    abstract::Several derivatives out of a series of antifungal agents exhibited a good inhibitory potency against aromatase as well as a fairly good selectivity toward CYP17, even if lacking H-bond accepting substituents. Their common structural feature is a flexible backbone that did not fit into previously reported CYP19 models....

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Castellano S,Stefancich G,Ragno R,Schewe K,Santoriello M,Caroli A,Hartmann RW,Sbardella G

    更新日期:2008-09-15 00:00:00

  • Synthesis and antihyperglycemic activity of suitably functionalized 3H-quinazolin-4-ones.

    abstract::A series of 2-sec-amino-3H-quinazolin-4-ones (4a-p) and 4-sec-amino-2-chloroquinazolines (5a-b) have been synthesized by nucleophilic substitution reaction of 2-chloro-4(3H)-quinazolones (3) and 2,4-dichloroquinazolines (2) with amines, respectively. Most of the synthesized compounds were evaluated for antihyperglycem...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ram VJ,Farhanullah,Tripathi BK,Srivastava AK

    更新日期:2003-05-29 00:00:00

  • Arylazolyl(azinyl)thioacetanilides. Part 16: Structure-based bioisosterism design, synthesis and biological evaluation of novel pyrimidinylthioacetanilides as potent HIV-1 inhibitors.

    abstract::A series of novel pyrimidinylthioacetanilides were designed, synthesized, and evaluated for their biological activity as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Most of the tested compounds were proved to be effective in inhibiting HIV-1 (IIIB) replication with EC50 ranging from 0.15 μM ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Li X,Lu X,Chen W,Liu H,Zhan P,Pannecouque C,Balzarini J,De Clercq E,Liu X

    更新日期:2014-10-01 00:00:00

  • The molecular structure of 2alpha-hydroxyneoanisatin and structure-activity relationships among convulsant sesquiterpenes of the seco-prezizaane and picrotoxane types.

    abstract::The molecular structure of 2alpha-hydroxyneoanisatin, a positional isomer of the potent neurotoxin anisatin, was determined by X-ray crystallographic analysis. This compound and four further seco-prezizaane type sesquiterpene lactones previously isolated from Illicium floridanum, which represent different structural t...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Schmidt TJ,Okuyama E,Fronczek FR

    更新日期:1999-12-01 00:00:00

  • Synthesis and antiprotozoal activity of dicationic 2,6-diphenylpyrazines and aza-analogues.

    abstract::Dicationic 2,6-diphenylpyrazines, aza-analogues and prodrugs were synthesized; evaluated for DNA affinity, activity against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) in vitro, efficacy in T. b. r. STIB900 acute and T. b. brucei GVR35 CNS mouse models. Most diamidines gave poly(dA-dT)2...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Hu L,Patel A,Bondada L,Yang S,Wang MZ,Munde M,Wilson WD,Wenzler T,Brun R,Boykin DW

    更新日期:2013-11-01 00:00:00

  • Cyclic MOG35-55 ameliorates clinical and neuropathological features of experimental autoimmune encephalomyelitis.

    abstract::EAE is induced to susceptible mice using linear peptides of myelin proteins of the central nervous system. Specific peptide motifs within the peptide-binding groove of the MHC peptide-complex determines the affinity of the peptide in each animal and the consequent T-cell receptor recognition and activation of the cell...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Lourbopoulos A,Deraos G,Matsoukas MT,Touloumi O,Giannakopoulou A,Kalbacher H,Grigoriadis N,Apostolopoulos V,Matsoukas J

    更新日期:2017-08-01 00:00:00

  • Characterization of chemical, radiochemical and optical properties of a dual-labeled MMP-9 targeting peptide.

    abstract::Optical imaging possesses similar sensitivity to nuclear imaging and has led to the emergence of multimodal approaches with dual-labeled nuclear/near-infrared (NIR) agents. The growing impact of (68)Ga (t(1/2)=68 min) labeled peptides on preclinical and clinical research offers a promising opportunity to merge the hig...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Azhdarinia A,Wilganowski N,Robinson H,Ghosh P,Kwon S,Lazard ZW,Davis AR,Olmsted-Davis E,Sevick-Muraca EM

    更新日期:2011-06-15 00:00:00

  • The tyrosinase inhibitory effects of isoxazolone derivatives with a (Z)-β-phenyl-α, β-unsaturated carbonyl scaffold.

    abstract::Thirteen (Z)-4-(substituted benzylidene)-3-phenylisoxazol-5(4H)-ones were designed to confirm the geometric effect of the double bond of the β-phenyl-α, β-unsaturated carbonyl scaffold on tyrosinase inhibitory activity. Compounds 1a-1m, which all possessed the (Z)-β-phenyl-α, β-unsaturated carbonyl scaffold, were synt...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Kim SJ,Yang J,Lee S,Park C,Kang D,Akter J,Ullah S,Kim YJ,Chun P,Moon HR

    更新日期:2018-08-07 00:00:00

  • Kinetic controlled affinity labeling of target enzyme with thioester chemistry.

    abstract::High specificity has been an important feature in affinity labeling for target profiling. Especially, to label targets via rapidly progressing reactions with consumption of ligand (probe), high specificity of reaction with common functional groups of target protein should be achieved without reactions with similar gro...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Tomohiro T,Nakabayashi M,Sugita Y,Morimoto S

    更新日期:2016-08-01 00:00:00

  • A spectroscopy approach for the study of the interactions of bioactive vanadium species with bovine serum albumin.

    abstract::The interest in biological functions (benefits or toxics effects) of vanadium species has grown enormously in recent years. In this work, different spectroscopic methods were applied to study the effects of the interaction of vanadyl and vanadate species with bovine serum albumin (BSA), considered as the most abundant...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ferrer EG,Bosch A,Yantorno O,Baran EJ

    更新日期:2008-04-01 00:00:00

  • Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs.

    abstract::Two new series of symmetric acyclic nucleoside bisphosphonates (ANbPs) have been synthesised as potential inhibitors of the Plasmodium falciparum (Pf) and vivax (Pv) 6-oxopurine phosphoribosyltransferases. The structural variability between these symmetric ANbPs lies in the number of atoms in the two acyclic linkers c...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Špaček P,Keough DT,Chavchich M,Dračínský M,Janeba Z,Naesens L,Edstein MD,Guddat LW,Hocková D

    更新日期:2017-08-01 00:00:00

  • The synthesis and anti-proliferative effects of beta-elemene derivatives with mTOR inhibition activity.

    abstract::Fourteen beta-elemene derivatives containing a piperazine, a morpholine, a tetrahydropyrrole, a thiophenylethylamine, or a cyclohexamine group were synthesized. The structures of these beta-elemene derivatives were characterized with IR, 1H NMR, MS, and elemental analyses. All these derivatives had an increased anti-p...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Xu L,Tao S,Wang X,Yu Z,Wang M,Chen D,Jing Y,Dong J

    更新日期:2006-08-01 00:00:00

  • Synthesis 4-[2-(2-mercapto-4-oxo-4H-quinazolin-3-yl)-ethyl]-benzenesulfonamides with subnanomolar carbonic anhydrase II and XII inhibitory properties.

    abstract::Condensation of substituted anthranilic acids with 4-isothiocyanatoethyl-benzenesulfonamide led to series of heterocyclic benzenesulfonamides incorporating 2-mercapto-quinazolin-4-one tails. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC isoforms hCA I and II (cyto...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Bozdag M,Alafeefy AM,Carta F,Ceruso M,Al-Tamimi AS,Al-Kahtani AA,Alasmary FAS,Supuran CT

    更新日期:2016-09-15 00:00:00

  • Molecular docking identifies the binding of 3-chloropyridine moieties specifically to the S1 pocket of SARS-CoV Mpro.

    abstract::The 3C-like main proteinase of the severe acute respiratory syndrome (SARS) coronavirus, SARS-CoV M(pro), is widely considered to be a major drug target for the development of anti-SARS treatment. Based on the chemical structure of a lead compound from a previous screening, we have designed and synthesized a number of...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Niu C,Yin J,Zhang J,Vederas JC,James MN

    更新日期:2008-01-01 00:00:00

  • Synthesis of new 18F-radiolabeled silicon-based nitroimidazole compounds.

    abstract::The syntheses of new nitroimidazole compounds using silicon-[(18)F]fluorine chemistry for the potential detection of tumor hypoxia are described. [(18)F]silicon-based compounds were synthesized by coupling 2-nitroimidazole with silyldinaphtyl or silylphenyldi-tert-butyl groups and labeled by fluorolysis or isotopic ex...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Joyard Y,Azzouz R,Bischoff L,Papamicaël C,Labar D,Bol A,Bol V,Vera P,Grégoire V,Levacher V,Bohn P

    更新日期:2013-07-01 00:00:00

  • Ophiobolin M and analogues, noncompetitive inhibitors of ivermectin binding with nematocidal activity.

    abstract::A series of ophiobolins were isolated from a fungal extract based on their nematocidal activity. These compounds are non-competitive inhibitors of ivermectin binding to membranes prepared from the free-living nematode, Caenorhabditis elegans, with an inhibition constant of 15 microM. The ophiobolins which were most po...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Tsipouras A,Adefarati AA,Tkacz JS,Frazier EG,Rohrer SP,Birzin E,Rosegay A,Zink DL,Goetz MA,Singh SB,Schaeffer JM

    更新日期:1996-04-01 00:00:00

  • Novel 3,6-bis(imidazolidine)acridines as effective photosensitizers for photodynamic therapy.

    abstract::The photoeffect of new proflavine derivatives with DNA-binding and antitumour activities, 3,6-bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides (AcrDIMs), was studied to evaluate them as potential photosensitizers for photodynamic antitumor therapy. EPR measurements showed that superoxide radical ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Cižeková L,Grolmusová A,Ipóthová Z,Barbieriková Z,Brezová V,Hunáková L,Imrich J,Janovec L,Dovinová I,Paulíková H

    更新日期:2014-09-01 00:00:00

  • Simple molecular engineering of glycol nucleic acid: progression from self-pairing to cross-pairing with cDNA and RNA.

    abstract::The acyclic chiral nucleic acid analogue, Glycol Nucleic Acid (GNA), displayed exceptional structural simplicity and atom economy while forming self-paired duplexes, using canonical Watson-Crick base pairing. We disclose here that the replacement of phosphodiester linker in GNA with somewhat rigid and shorter carbamat...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Bose T,Kumar VA

    更新日期:2014-11-01 00:00:00

  • Synthesis, structural analysis and antitumor activity of novel 17α-picolyl and 17(E)-picolinylidene A-modified androstane derivatives.

    abstract::The heterocyclic ring at C-17 position of the androstane compounds plays an important role in biological activity. The aim of the present study was to synthesize and evaluate potential antitumor activity of different A-modified 17α-picolyl and 17(E)-picolinylidene androstane derivatives. In several synthetic steps, no...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ajduković JJ,Penov Gaši KM,Jakimov DS,Klisurić OR,Jovanović-Šanta SS,Sakač MN,Aleksić LD,Djurendić EA

    更新日期:2015-04-01 00:00:00

  • Design, synthesis and bioactivities of Celecoxib analogues or derivatives.

    abstract::A series of Celecoxib analogues or derivatives were designed and synthesized, and their biological activities were studied. The results of inhibitory activity in vitro proved that compounds 1a, 1h, 1i, 1l and 1p had better inhibitory effect on COX-2, and the selectivity was higher. Among them, the inhibitory activity ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Zhou S,Yang S,Huang G

    更新日期:2017-09-01 00:00:00

  • Acidic biphenyl derivatives: synthesis and biological activity of a new series of potent 5-HT(4) receptor antagonists.

    abstract::Serotonin (5-hydroxytryptamine, 5-HT) is an important signaling molecule in the central nervous system (CNS) and in non-neuronal tissues and organs. Serotonin mediates a positive chronotropic and inotropic response through 5-HT4 receptors in the atrium and ventricle of the heart. Recent investigations have revealed in...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Brudeli B,Andressen KW,Moltzau LR,Nilsen NO,Levy FO,Klaveness J

    更新日期:2013-11-15 00:00:00

  • Design, synthesis, and biological characterization of novel PEG-linked dimeric modulators for CXCR4.

    abstract::CXCR4 dimerization has been widely demonstrated both biologically and structurally. This paper mainly focused on the development of structure-based dimeric ligands that target CXCL12-CXCR4 interaction and signaling. This study presents the design and synthesis of a series of [PEG]n linked dimeric ligands of CXCR4 base...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Yang Y,Gao M,Zhang Q,Zhang C,Yang X,Huang Z,An J

    更新日期:2016-11-01 00:00:00

  • RO4383596, an orally active KDR, FGFR, and PDGFR inhibitor: synthesis and biological evaluation.

    abstract::(+/-)-1-(anti-3-Hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (RO4383596) is a potent and selective inhibitor of the pro-angiogenic receptor tyrosine kinases KDR, FGFR, and PDGFR. This agent has an excellent pharmacokinetic profile and is highly efficacious in ro...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: McDermott LA,Simcox M,Higgins B,Nevins T,Kolinsky K,Smith M,Yang H,Li JK,Chen Y,Ke J,Mallalieu N,Egan T,Kolis S,Railkar A,Gerber L,Luk KC

    更新日期:2005-08-15 00:00:00

  • Synthesis and binding affinities of fluoroalkylated raloxifenes.

    abstract::Three fluoroalkylated derivatives (1-3) of the selective estrogen receptor modulator (SERM), raloxifene, have been synthesized. The key step in the synthesis is the C-C bond formation of benzo[b]thiophene and a substituted phenyl group (ring C) using a Stille reaction. The in vitro binding affinities of the substitute...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Lee KC,Moon BS,Lee JH,Chung KH,Katzenellenbogen JA,Chi DY

    更新日期:2003-08-15 00:00:00

  • Synthetic strategies toward carbocyclic purine-pyrimidine hybrid nucleosides.

    abstract::The blending of key structural features from the purine and pyrimidine nucleobase scaffolds gives rise to a new class of hybrid nucleosides. The purine-pyrimidine hybrid nucleosides can be viewed as either N-3 ribosylated purines or 5,6-disubstituted pyrimidines, thus recognition by both purine- and pyrimidine-metabol...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Sadler JM,Mosley SL,Dorgan KM,Zhou ZS,Seley-Radtke KL

    更新日期:2009-08-01 00:00:00

  • Design and synthesis of labeled analogs of PhTX-56, a potent and selective AMPA receptor antagonist.

    abstract::Polyamines and polyamine toxins are biologically important molecules, having modulatory effects on nucleotides and proteins. The wasp toxin, philanthotoxin-433 (PhTX-433), is a non-selective and uncompetitive antagonist of ionotropic receptors, such as ionotropic glutamate receptors and nicotinic acetylcholine recepto...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Andersen TF,Vogensen SB,Jensen LS,Knapp KM,Strømgaard K

    更新日期:2005-09-01 00:00:00