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














  • Criteria for the mode of binding of DNA binding agents.

    abstract::A complete characterization of DNA binding agents requires that their mode of binding to DNA be established. In the absence of high resolution structural data, the mode of binding is, of necessity, usually inferred indirectly from various solution studies. The purpose of this study is to show that only certain methods...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Suh D,Chaires JB

    更新日期:1995-06-01 00:00:00

  • Synthesis and biological evaluation of all eight stereoisomers of DPP-IV inhibitor saxagliptin.

    abstract::All eight stereoisomers of saxagliptin have been synthesized and evaluated for their inhibitory activity against DPP-IV. It was unambiguously confirmed that the configuration of saxagliptin was critical to potent inhibition of DPP-IV. Docking study was performed to elucidate the configuration-activity relationship of ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Dong J,Gong Y,Liu J,Chen X,Wen X,Sun H

    更新日期:2014-02-15 00:00:00

  • Inhibitory activity of Brazilian green propolis components and their derivatives on the release of cys-leukotrienes.

    abstract::The effects of Brazilian green propolis ethanol extract on Cry j1-induced cys-leukotrienes and histamine release from peripheral leukocytes of patients with allergic rhinitis were investigated. One of the key mechanisms for the anti-allergic properties of the extract was revealed to be the suppression of cys-LTs relea...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Tani H,Hasumi K,Tatefuji T,Hashimoto K,Koshino H,Takahashi S

    更新日期:2010-01-01 00:00:00

  • Large scale preparation of chiral building blocks for the P3 site of renin inhibitors.

    abstract::Racemic ethyl 2-benzyl-3-(tert-butylsulfonyl)propionate (1) and racemic ethyl 2-benzyl-3-[[1-methyl-1-((morpholin-4-yl)carbonyl)ethyl]sulfonyl] propionate (3) were enantioselectively hydrolyzed by subtilisin Carlsberg generating the respective (S)-acids used as building blocks for renin inhibitors. The esters were rea...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Doswald S,Estermann H,Kupfer E,Stadler H,Walther W,Weisbrod T,Wirz B,Wostl W

    更新日期:1994-06-01 00:00:00

  • On the topological evidences for modelling lipophilicity.

    abstract::Topological evidences for modelling lipophilicity of a large series of diversed compounds have been provided on the basis of distance-based topological indices. A pool of topological indices along with indicator parameters related to the type of the compounds present in the set of 140 compounds were used for this purp...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Agrawal VK,Singh J,Khadikar PV

    更新日期:2002-12-01 00:00:00

  • Design, synthesis and antibacterial study of new potent and selective coumarin-chalcone derivatives for the treatment of tenacibaculosis.

    abstract::With the aim of finding new chemical entities selective for fish pathogens to avoid drug resistance in humans, a series of coumarin-chalcone hybrid compounds with different patterns of substitution were designed and synthesized. Their antibacterial activity was evaluated against important types of human bacteria strai...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Vazquez-Rodriguez S,Lama López R,Matos MJ,Armesto-Quintas G,Serra S,Uriarte E,Santana L,Borges F,Muñoz Crego A,Santos Y

    更新日期:2015-11-01 00:00:00

  • Pharmacodynamics and pharmacokinetics studies of phenoxazinium derivatives for antimalarial agent.

    abstract::In vivo antimalarial drug candidates screening test was carried out on a series of water-soluble 3,7-bis(dialkylamino)phenoxazin-5-ium derivatives. Among them, 3-(diethylamino)-7-(piperidin-1-yl)phenoxazin-5-ium chloride (SSJ-206) showing highest efficacy was chosen for further pharmcodynamics and pharmacokinetics stu...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Yang M,Ge JF,Arai C,Itoh I,Fu Q,Ihara M

    更新日期:2009-02-15 00:00:00

  • Antimicrobial and cytotoxic arylazoenamines. Part III: antiviral activity of selected classes of arylazoenamines.

    abstract::Eighty-five arylazoenamines, characterized by different types of aryl and basic moieties, have been synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of ten RNA and DNA viruses. The most commonly affected viruses were, in decreasing order, CVB-2, RSV, BVDV, YFV, and...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Tonelli M,Boido V,Canu C,Sparatore A,Sparatore F,Paneni MS,Fermeglia M,Pricl S,La Colla P,Casula L,Ibba C,Collu D,Loddo R

    更新日期:2008-09-15 00:00:00

  • Glycosyl bis-porphyrin conjugates: synthesis and potential application in PDT.

    abstract::Syntheses of new glycosylated neutral and cationic porphyrin dimers linked at the meso-position via a flexible hydrocarbon chain are described. A detailed 1H and 13C NMR study allows their complete structural elucidation. The UV-visible, fluorescence and MALDI mass spectra are also presented. Photocytotoxicities of th...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Sol V,Chaleix V,Champavier Y,Granet R,Huang YM,Krausz P

    更新日期:2006-12-01 00:00:00

  • SAR of a series of anti-HSV-1 acridone derivatives, and a rational acridone-based design of a new anti-HSV-1 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine series.

    abstract::Herpes Simplex Virus (HSV) infections are among the most common human diseases. In this work, we assess the structural features and electronic properties of a series of ten 1-hydroxyacridone derivatives (1a-j) recently described as a new class of non-nucleoside inhibitors of Herpes Simplex Virus-1 (HSV-1). Based on th...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Bernardino AM,Castro HC,Frugulhetti IC,Loureiro NI,Azevedo AR,Pinheiro LC,Souza TM,Giongo V,Passamani F,Magalhães UO,Albuquerque MG,Cabral LM,Rodrigues CR

    更新日期:2008-01-01 00:00:00

  • Protein linear indices of the 'macromolecular pseudograph alpha-carbon atom adjacency matrix' in bioinformatics. Part 1: prediction of protein stability effects of a complete set of alanine substitutions in Arc repressor.

    abstract::A novel approach to bio-macromolecular design from a linear algebra point of view is introduced. A protein's total (whole protein) and local (one or more amino acid) linear indices are a new set of bio-macromolecular descriptors of relevance to protein QSAR/QSPR studies. These amino-acid level biochemical descriptors ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Marrero-Ponce Y,Medina-Marrero R,Castillo-Garit JA,Romero-Zaldivar V,Torrens F,Castro EA

    更新日期:2005-04-15 00:00:00

  • Biodistribution of (125)I-labeled polymeric vaccine carriers after subcutaneous injection.

    abstract::Polymeric nanoparticles (NPs) comprised of hydrophilic poly(γ-glutamic acid) in the main chain and hydrophobic phenylalanine in the side chain (γ-PGA-Phe) are a promising vaccine carrier for various kinds of diseases. However, little is known about the fate of subcutaneously administered γ-PGA-Phe NPs. Therefore, we n...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Toita R,Kanai Y,Watabe H,Nakao K,Yamamoto S,Hatazawa J,Akashi M

    更新日期:2013-09-01 00:00:00

  • Design and synthesis of novel pyrimido[4,5-b]azepine derivatives as HER2/EGFR dual inhibitors.

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    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Kawakita Y,Seto M,Ohashi T,Tamura T,Yusa T,Miki H,Iwata H,Kamiguchi H,Tanaka T,Sogabe S,Ohta Y,Ishikawa T

    更新日期:2013-04-15 00:00:00

  • Synthesis and biological evaluation of di-aryl urea derivatives as c-Kit inhibitors.

    abstract::Inhibition of receptor tyrosine kinases (RTKs) continued to be a successful approach for the treatment of many types of human cancers and many potent small molecules kinase inhibitors have been discovered the last decade. In the present study, we describe the synthesis of thienopyrimidine derivatives and their pharmac...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ravez S,Arsenlis S,Barczyk A,Dupont A,Frédérick R,Hesse S,Kirsch G,Depreux P,Goossens L

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  • 3-Amino-2(5H)furanones as inhibitors of subgenomic hepatitis C virus RNA replication.

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    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Iannazzo D,Piperno A,Romeo G,Romeo R,Chiacchio U,Rescifina A,Balestrieri E,Macchi B,Mastino A,Cortese R

    更新日期:2008-11-01 00:00:00

  • Structure-activity relationship and biological property of cortistatins, anti-angiogenic spongean steroidal alkaloids.

    abstract::Previously, bioassay-guided separation led us to isolate eleven novel steroidal alkaloids named cortistatins from the marine sponge Corticium simplex. These cortistatins were classified into three types based on the chemical structure of the side chain part, that is, isoquinoline, N-methyl piperidine or 3-methylpyridi...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Aoki S,Watanabe Y,Tanabe D,Arai M,Suna H,Miyamoto K,Tsujibo H,Tsujikawa K,Yamamoto H,Kobayashi M

    更新日期:2007-11-01 00:00:00

  • Broad-spectrum antimicrobial activity of hemoglobin.

    abstract::While hemoglobin is one of the most well characterized proteins due to its function in oxygen transport, few additional properties of hemoglobin have been described. While screening serum samples for novel antimicrobial factors, it was found that intact hemoglobin tetramers, including that from human, exhibited consid...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Parish CA,Jiang H,Tokiwa Y,Berova N,Nakanishi K,McCabe D,Zuckerman W,Xia MM,Gabay JE

    更新日期:2001-02-01 00:00:00

  • Catechol derivatives of aminopyrazine and cell protection against UVB-induced mortality.

    abstract::A series of 5-aryl- and 3,5-bis-aryl-2-amino-1,4-pyrazine derivatives 4 and 6, and related imidazolopyrazinones 7, has been synthesized, the aryl groups of which are catechol and/or phenol substituents. These compounds, tested against human keratinocyte cells stressed by UVB irradiation, showed high antioxidative prop...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Cavalier JF,Burton M,Dussart F,Marchand C,Rees JF,Marchand-Brynaert J

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    abstract::A novel series of 2-thiocarbamoyl-2,3,4,5,6,7-hexahydro-1H-indazole and 2-substituted thiocarbamoyl-3,3a,4,5,6,7-hexahydro-2H-indazoles derivatives were synthesized and investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). The target molecules were identified on the b...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Gökhan-Kelekçi N,Simşek OO,Ercan A,Yelekçi K,Sahin ZS,Işik S,Uçar G,Bilgin AA

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    abstract::It was envisaged to combine high antipyretic activity of paracetamol into commonly used NSAIDs. To achieve this goal new chemical entities were synthesized by chemically combining paracetamol and NSAIDs, and biologically evaluated for their antipyretic, analgesic, anti-inflammatory and ulcerogenic potential. The acid ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Yadav MR,Nimekar DM,Ananthakrishnan A,Brahmkshatriya PS,Shirude ST,Giridhar R,Parmar A,Balaraman R

    更新日期:2006-12-15 00:00:00

  • Design, synthesis, and evaluation of non-steroidal farnesoid X receptor (FXR) antagonist.

    abstract::A series of substituted-isoxazole derivatives was prepared as candidate farnesoid X receptor (FXR) antagonists, based on our previously proposed ligand superfamily concept. Structure-activity relationship studies indicated that the shape and the structural bulkiness of the substituent at the 5-position of the isoxazol...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Kainuma M,Makishima M,Hashimoto Y,Miyachi H

    更新日期:2007-04-01 00:00:00

  • Mapping of possible binding sequences of two beta-sheet breaker peptides on beta amyloid peptide of Alzheimer's disease.

    abstract::Aggregation of amyloid peptide (Abeta) has been identified as a major feature of the pathogenesis of Alzheimer's disease. Increased risk for disease is associated with increased formation of polymerized Abeta. Inhibition of formation of toxic (aggregated) form of Abeta is one of the therapeutic possibilities. Beta she...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Hetényi C,Körtvélyesi T,Penke B

    更新日期:2002-05-01 00:00:00

  • 3-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporter.

    abstract::CNS diseases such as Parkinson, schizophrenia, and attention deficit hyperactivity disorder (ADHD) are characterized by a significant alteration of dopamine transporter (DAT) density. Thus, the development of compounds that are able to selectively interact with DAT is of great interest. Herein we describe the design a...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Cini N,Danieli E,Menchi G,Trabocchi A,Bottoncetti A,Raspanti S,Pupi A,Guarna A

    更新日期:2006-08-01 00:00:00

  • A simple synthesis of four stereoisomers of roseoside and their inhibitory activity on leukotriene release from mice bone marrow-derived cultured mast cells.

    abstract::Four stereoisomers of roseoside (vomifoliol glucosides) were synthesized using glucose as a chiral resolving reagent. The four synthetic stereoisomers exhibited inhibitory activity on leukotriene release from mouse bone marrow-derived cultured mast cells (BMCMC). The (6S)-isomers of roseoside were about twice as activ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Yajima A,Oono Y,Nakagawa R,Nukada T,Yabuta G

    更新日期:2009-01-01 00:00:00

  • Selective inhibition of β-N-acetylhexosaminidases by thioglycosyl-naphthalimide hybrid molecules.

    abstract::To develop selective inhibitors for β-N-acetylhexosaminidases which are involved in a myriad of physiological processes, a series of novel thioglycosyl-naphthalimide hybrid inhibitors were designed, synthesized and evaluated for inhibition activity against glycosyl hydrolase family 20 and 84 (GH20 and GH84) β-N-acetyl...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Chen W,Shen S,Dong L,Zhang J,Yang Q

    更新日期:2018-01-15 00:00:00

  • 6-amino-4-oxo-1,3-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl derivatives as a new class of potent inhibitors of Interleukin-8-induced neutrophil chemotaxis.

    abstract::A series of 6-amino-4-oxo-1,3-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl derivatives was synthesized. The compounds demonstrated to be novel, potent and selective inhibitors of Interleukin-8-induced human neutrophil chemotaxis. A SAR study was performed by varying the carbonyl function at position 5 and...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Cesarini S,Spallarossa A,Ranise A,Bruno O,Arduino N,Bertolotto M,Dallegri F,Tognolini M,Gobbetti T,Barocelli E

    更新日期:2009-05-15 00:00:00

  • Design, synthesis and biological activity evaluation of desloratadine analogues as H1 receptor antagonists.

    abstract::A series of N-substituted desloratadine analogues were designed and synthesized. They were tested for H1 antihistamine activity by inhibiting histamine-induced contraction of isolated ileum muscles of guinea-pigs in vitro and inhibiting histamine-induced asthmatic reaction in guinea-pigs in vivo. All the evaluated com...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Lin Y,Wang Y,Sima LF,Wang DH,Cao XH,Chen LG,Chen B

    更新日期:2013-07-15 00:00:00

  • A new peptidyl fluorescent chemosensors for the selective detection of mercury ions based on tetrapeptide.

    abstract::A novel peptidyl chemosensor (PySO2-His-Gly-Gly-Lys(PySO2)-NH2, 1) was synthesized by incorporation of two pyrene (Py) fluorophores into the tetrapeptide using sulfonamide group. Compound 1 exhibited selective fluorescence response towards Hg(II) over the other metal ions in aqueous buffered solutions. Furthermore, 1 ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Thirupathi P,Lee KH

    更新日期:2013-12-15 00:00:00

  • 1,2,3,4-tetrahydroisoquinoline derivatives: a new class of 5-HT1A receptor ligands.

    abstract::Three series of new N-substituted 1,2,3,4-tetrahydroisoquinolines with 2-, 3-, and 4-membered alkyl chains (a, b, and c, respectively) were synthesized, and the effect of some structural modifications on their 5-HT1A receptor affinities and functional properties was discussed. It was found that the volume of the termi...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Mokrosz MJ,Bojarski AJ,Duszyńska B,Tatarczyńska E,Kłodzińska A,Dereń-Wesołek A,Charakchieva-Minol S,Chojnacka-Wójcik E

    更新日期:1999-02-01 00:00:00

  • New acridone-4-carboxylic acid derivatives as potential inhibitors of hepatitis C virus infection.

    abstract::A new class of compounds--acridone derivatives--was tested using the direct fluorometric helicase activity assay to determine the inhibitory properties of the derivatives towards the NS3 helicase of Hepatitis C virus (HCV). The compounds were also tested as putative transcription inhibitors of in vitro transcription b...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Stankiewicz-Drogon A,Palchykovska LG,Kostina VG,Alexeeva IV,Shved AD,Boguszewska-Chachulska AM

    更新日期:2008-10-01 00:00:00