当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY期刊下所有文献 > Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor.

Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor.

Abstract：

:Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assays. Chemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Hamaguchi H,Amano Y,Moritomo A,Shirakami S,Nakajima Y,Nakai K,Nomura N,Ito M,Higashi Y,Inoue T

doi

10.1016/j.bmc.2018.08.005

subject

Has Abstract

pub_date

2018-10-01 00:00:00

pages

4971-4983

issue

18

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(18)31300-2

journal_volume

26

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY文献大全
  • Design, synthesis and anticonvulsant properties of new N-Mannich bases derived from 3-phenylpyrrolidine-2,5-diones.

    abstract：:The synthesis and anticonvulsant properties of new N-Mannich bases of 3-phenyl- (9a-d), 3-(2-chlorophenyl)- (10a-d), 3-(3-chlorophenyl)- (11a-d) and 3-(4-chlorophenyl)-pyrrolidine-2,5-diones (12a-d) were described. The key synthetic strategies involve the formation of 3-substituted pyrrolidine-2,5-diones (5-8), and th...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.07.029

    authors： Kamiński K,Obniska J,Chlebek I,Wiklik B,Rzepka S

    更新日期：2013-11-01 00:00:00

  • Carbon-11 labeled indolylpropylamine analog as a new potential PET agent for imaging of the serotonin transporter.

    abstract：:The synthesis and structure-activity relationship of a new class of indole derivatives with low-nanomolar affinity for the SERT and high selectivity versus the 5-HT1A receptor were recently reported. Based on their chemical structure, four new indolylpropylamine derivatives which contain atoms to afford future labelin...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.05.006

    authors： Ben-Daniel R,Deuther-Conrad W,Scheunemann M,Steinbach J,Brust P,Mishani E

    更新日期：2008-06-15 00:00:00

  • Synthesis and proteasome inhibition of glycyrrhetinic acid derivatives.

    abstract：:This study discovered that glycyrrhetinic acid inhibited the human 20S proteasome at 22.3microM. Esterification of the C-3 hydroxyl group on glycyrrhetinic acid with various carboxylic acid reagents yielded a series of analogs with marked improved potency. Among the derivatives, glycyrrhetinic acid 3-O-isophthalate (1...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.05.078

    authors： Huang L,Yu D,Ho P,Qian K,Lee KH,Chen CH

    更新日期：2008-07-15 00:00:00

  • Total synthesis and a systematic structure-activity relationship study of WAP-8294A2.

    abstract：:WAP-8294A2 is a cyclic peptide antibiotic with novel structure and excellent activity against Gram-positive pathogens. Herein, we report the total synthesis of complex macrocyclic peptide WAP-8294A2 (W1), ent-analogue W2, deoxy analogue W3 and de-methyl analogue W4 using a solid-phase synthetic route followed by a fin...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2020.115677

    authors： Chen D,Tian L,Po KHL,Chen S,Li X

    更新日期：2020-09-15 00:00:00

  • Identification of a new class of potent Cdc7 inhibitors designed by putative pharmacophore model: Synthesis and biological evaluation of 2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-ones.

    abstract：:Cell division cycle 7 (Cdc7) is a serine/threonine kinase that plays important roles in the regulation of DNA replication process. A genetic study indicates that Cdc7 inhibition can induce selective tumor-cell death in a p53-dependent manner, suggesting that Cdc7 is an attractive target for the treatment of cancers. I...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2017.02.021

    authors： Kurasawa O,Oguro Y,Miyazaki T,Homma M,Mori K,Iwai K,Hara H,Skene R,Hoffman I,Ohashi A,Yoshida S,Ishikawa T,Cho N

    更新日期：2017-04-01 00:00:00

  • Synthesis and biological activities of novel antiallergic agents with 5-lipoxygenase inhibiting action.

    abstract：:Novel benzimidazole derivatives were synthesized and their pharmacological activities were examined. These compounds showed a good suppressive action on histamine release from rat peritoneal mast cells produced by antigen-antibody reaction, an antagonistic action on guinea pig ileum contraction caused by histamine, an...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(99)00291-6

    authors： Nakano H,Inoue T,Kawasaki N,Miyataka H,Matsumoto H,Taguchi T,Inagaki N,Nagai H,Satoh T

    更新日期：2000-02-01 00:00:00

  • Effect of single pyrrole replacement with β-alanine on DNA binding affinity and sequence specificity of hairpin pyrrole/imidazole polyamides targeting 5'-GCGC-3'.

    abstract：:N-Methylpyrrole (Py)-N-methylimidazole (Im) polyamides are small organic molecules that can recognize predetermined DNA sequences with high sequence specificity. As many eukaryotic promoter regions contain highly GC-rich sequences, it is valuable to synthesize and characterize Py-Im polyamides that recognize GC-rich m...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.06.005

    authors： Han YW,Kashiwazaki G,Morinaga H,Matsumoto T,Hashiya K,Bando T,Harada Y,Sugiyama H

    更新日期：2013-09-01 00:00:00

  • Metabolites of orally active NO-independent pyrazolopyridine stimulators of soluble guanylate cyclase.

    abstract：:The pyrazolopyridine stimulators of soluble guanylate cyclase BAY 41-2272 and 41-8543 were oxidised in rats and dogs at their 5-pyrimidinyl-cyclopropyl and -morpholino residue. These metabolites activate the soluble guanylate cyclase, induce vasoelaxation and thereby may contribute to the in vivo activity of BAY 41-22...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(02)00034-2

    authors： Straub A,Benet-Buckholz J,Fröde R,Kern A,Kohlsdorfer C,Schmitt P,Schwarz T,Siefert HM,Stasch JP

    更新日期：2002-06-01 00:00:00

  • Recognition of the DNA minor groove by pyrrole-imidazole polyamides: comparison of desmethyl- and N-methylpyrrole.

    abstract：:Polyamides consisting of N-methylpyrrole (Py), N-methylimidazole (Im), and N-methyl-3-hydroxypyrrole (Hp) are synthetic ligands that recognize predetermined DNA sequences with affinities and specificities comparable to many DNA-binding proteins. As derivatives of the natural products distamycin and netropsin, Py/Im/Hp...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(00)00145-0

    authors： Bremer RE,Szewczyk JW,Baird EE,Dervan PB

    更新日期：2000-08-01 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

    doi：10.1016/s0968-0896(97)00176-4

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

    更新日期：1998-01-01 00:00:00

  • Synthesis and biological activities of quinazoline derivatives with ortho-phenol-quaternary ammonium salt groups.

    abstract：:One phenol-quaternary ammonium salt derivative with a flexible linker and three derivatives with a quinazoline moiety are present. Their binding affinities for DNA are discussed and it is clearly demonstrated that this class of phenol-quaternary ammonium salt derivatives could inhibit DNA transcription effectively. ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2007.07.053

    authors： Zhang L,Ren L,Bai M,Weng L,Huang J,Wu L,Deng M,Zhou X

    更新日期：2007-11-15 00:00:00

  • Design, synthesis, and biological evaluation of 1,3-diarylprop-2-en-1-ones : a novel class of cyclooxygenase-2 inhibitors.

    abstract：:A group of regioisomeric (E)-1,3-diarylprop-2-en-1-one derivatives possessing a COX-2 SO2Me pharmacophore at the para position of the C-1 or C-3 phenyl ring, in conjunction with a C-3 or C-1 phenyl (4-H) or substituted-phenyl ring (4-F, 4-OMe and 4-Me), were designed for evaluation as selective cyclooxygenase-2 (COX-2...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2005.11.041

    authors： Zarghi A,Arfaee S,Rao PN,Knaus EE

    更新日期：2006-04-15 00:00:00

  • Selective binding and controlled release of anticancer drugs by polyanionic cyclodextrins.

    abstract：:The binding stoichiometry, binding constants, and inclusion mode of some water-soluble negatively charged cyclodextrin derivatives, i.e. heptakis-[6-deoxy-6-(3-sulfanylpropanoic acid)]-β-cyclodextrin(H1), heptakis-[6-deoxy-6-(2-sulfanylacetic acid)]-β-cyclodextrin(H2), mono-[6-deoxy-6-(3-sulfanylpropanoic acid)]-β-cyc...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2018.03.013

    authors： Cheng JG,Yu HJ,Chen Y,Liu Y

    更新日期：2018-05-15 00:00:00

  • Novel quinazolinone derivatives as 5-HT7 receptor ligands.

    abstract：:5-HT(7) receptor antagonists generated antidepressant-like effects in animal model and the involvement of the 5-HT(7) receptor in other pathophysiological mechanisms such as thermoregulation, learning and memory, and sleep has been highlighted by various studies. As one of our efforts to discover a new type of 5-HT(7)...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2007.11.049

    authors： Na YH,Hong SH,Lee JH,Park WK,Baek DJ,Koh HY,Cho YS,Choo H,Pae AN

    更新日期：2008-03-01 00:00:00

  • Synthesis and structure-activity relationships of benzyloxyphenyl derivatives as a novel class of NCX inhibitors: effects on heart failure.

    abstract：:In the context of heart failure and myocardial ischemia reperfusion, the activity of the sodium-calcium exchanger can lead to calcium overload, which in turn can lead to contractile dysfunction and arrhythmia. Therefore, NCX is an attractive target for treatment of heart failure and myocardial ischemia reperfusion. We...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2004.10.048

    authors： Kuramochi T,Kakefuda A,Yamada H,Ogiyama T,Taguchi T,Sakamoto S

    更新日期：2005-02-01 00:00:00

  • A credit-card library approach for disrupting protein-protein interactions.

    abstract：:Protein-protein interfaces are prominent in many therapeutically important targets. Using small organic molecules to disrupt protein-protein interactions is a current challenge in chemical biology. An important example of protein-protein interactions is provided by the Myc protein, which is frequently deregulated in h...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2005.11.052

    authors： Xu Y,Shi J,Yamamoto N,Moss JA,Vogt PK,Janda KD

    更新日期：2006-04-15 00:00:00

  • Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors.

    abstract：:The β-lactam cholesterol absorption inhibitor ezetimibe is so far the only representative of this class of compounds on the market today. The goal of this work was to synthesize new amide ezetimibe analogs from trans-3-amino-(3R,4R)-β-lactam and to test their cytotoxicity and activity as cholesterol absorption inhibit...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2015.03.067

    authors： Dražić T,Sachdev V,Leopold C,Patankar JV,Malnar M,Hećimović S,Levak-Frank S,Habuš I,Kratky D

    更新日期：2015-05-15 00:00:00

  • 3-Phenyl substituted 6,7-dimethoxyisoquinoline derivatives as FtsZ-targeting antibacterial agents.

    abstract：:The emergence of multidrug-resistant bacteria has created an urgent need for antibiotics with a novel mechanism of action. The bacterial cell division protein FtsZ is an attractive target for the development of novel antibiotics. The benzo[c]phenanthridinium sanguinarine and the dibenzo[a,g]quinolizin-7-ium berberine ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2012.10.009

    authors： Kelley C,Zhang Y,Parhi A,Kaul M,Pilch DS,LaVoie EJ

    更新日期：2012-12-15 00:00:00

  • Synthesis, incorporation efficiency, and stability of disulfide bridged functional groups at RNA 5'-ends.

    abstract：:Modified guanosine monophosphates have been employed to introduce various functional groups onto RNA 5'-ends. Applications of modified RNA 5'-ends include the generation of functionalized RNA libraries for in vitro selection of catalytic RNAs, the attachment of photoaffinity-tags for mapping RNA-protein interactions o...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(00)00080-8

    authors： Sengle G,Jenne A,Arora PS,Seelig B,Nowick JS,Jäschke A,Famulok M

    更新日期：2000-06-01 00:00:00

  • Triterpene sapogenin-polyarginine conjugates exhibit promising antibacterial activity against Gram-positive strains.

    abstract：:Triterpene sapogenins are a group of biologically active compounds with antibacterial activity. However, the limited solubility and poor bioavailability of triterpene sapogenins restrict their therapeutic application. Polyarginine peptides are small cationic peptides with high affinities for multiple negatively charge...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2016.05.008

    authors： Na H,Li X,Zou C,Wang C,Wang C,Liu K

    更新日期：2016-07-01 00:00:00

  • Synthesis and in vitro characterization of platinum(II) anticancer coordinates using FTIR spectroscopy and NCI COMPARE: A fast method for new compound discovery.

    abstract：:Platinum-based drugs have been used for several decades to treat various cancers successfully. Cisplatin is the original compound in this class; it cross-links DNA, resulting in cell cycle arrest and cell death via apoptosis. Cisplatin is effective against several tumor types but exhibits toxic side effects; in additi...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2014.04.017

    authors： Berger G,Leclercqz H,Derenne A,Gelbcke M,Goormaghtigh E,Nève J,Mathieu V,Dufrasne F

    更新日期：2014-07-01 00:00:00

  • Synthesis and molecular modeling of some novel hexahydroindazole derivatives as potent monoamine oxidase inhibitors.

    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

    doi：10.1016/j.bmc.2009.07.033

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

    更新日期：2009-09-15 00:00:00

  • QSAR of the testosterone binding globulin affinity by means of correlation weighting of local invariants of the graph of atomic orbitals.

    abstract：:Numerical values of the testosterone binding globulin affinity have been modeled as a mathematical function of molecular structure in two versions of molecular structure elucidation: first, by hydrogen-filled molecular graphs (HFG); second, by the so-called graphs of atomic orbitals (GAO). Increased orders of Morgan e...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2005.07.059

    authors： Raska I Jr,Toropov A

    更新日期：2005-12-15 00:00:00

  • Fluorinated methylenecyclopropane analogues of nucleosides. Synthesis and antiviral activity of (Z)- and (E)-9-{[(2-fluoromethyl-2-hydroxymethyl)-cyclopropylidene]methyl}adenine and -guanine.

    abstract：:Synthesis and antiviral activity of the title fluoromethylenecyclopropane analogues 15a, 15b, 16a, and 16b is described. Methylenecyclopropane carboxylate was first transformed to 2,2-bis-hydroxymethylmethylenecyclopropane. Selective monoacetylation followed by introduction of fluorine gave 2-acetoxymethyl-2-fluoromet...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2007.11.082

    authors： Li C,Prichard MN,Korba BE,Drach JC,Zemlicka J

    更新日期：2008-03-01 00:00:00

  • Cytotoxicity mechanisms of pyrazino[1,2-b]isoquinoline-4-ones and SAR studies.

    abstract：:The cytotoxicity showed by 1b, an interesting representant of the title compounds, for HT-29 human colon cancer cells (CI(50) value of 1.95 x 10(-7)M) has been related to the induced cell death at the G2 phase and not to DNA damage. This compound promotes the degradation of components of the G2/M checkpoint machinery,...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2009.10.007

    authors： Ortín I,González JF,Cuesta Ede L,Manguan-García C,Perona R,Avendaño C

    更新日期：2009-12-01 00:00:00

  • Chemoselective fluorination and chemoinformatic analysis of griseofulvin: Natural vs fluorinated fungal metabolites.

    abstract：:Griseofulvin is a fungal metabolite and antifungal drug used for the treatment of dermatophytosis in both humans and animals. Recently, griseofulvin and its analogues have attracted renewed attention due to reports of their potential anticancer effects. In this study griseofulvin (1) and related analogues (2-6, with 4...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2017.07.041

    authors： Paguigan ND,Al-Huniti MH,Raja HA,Czarnecki A,Burdette JE,González-Medina M,Medina-Franco JL,Polyak SJ,Pearce CJ,Croatt MP,Oberlies NH

    更新日期：2017-10-15 00:00:00

  • Synthesis, structural elucidation and in vitro antiparasitic activity against Trypanosoma cruzi and Leishmania chagasi parasites of novel tetrahydro-1-benzazepine derivatives.

    abstract：:Forty six new 1,4-epoxy-2-exo-aryl- and cis-2-aryl-4-hydroxytetrahydro-1-benzazepine derivatives were synthesized and fully characterized. All compounds were tested in vitro against both Trypanosoma cruzi and Leishmania chagasi parasites and also for cytotoxicity using Vero and THP-1 mammalian cell lines. Many of the ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2010.05.018

    authors： Gómez-Ayala S,Castrillón JA,Palma A,Leal SM,Escobar P,Bahsas A

    更新日期：2010-07-01 00:00:00

  • Novel pyridyl nitrofuranyl isoxazolines show antibacterial activity against multiple drug resistant Staphylococcus species.

    abstract：:A novel series of pyridyl nitrofuranyl isoxazolines were synthesized and evaluated for their antibacterial activity against multiple drug resistant (MDR) Staphylococcus strains. Compounds with piperazine linker between the pyridyl group and isoxazoline ring showed better activity when compared to compounds without the...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2017.05.037

    authors： Picconi P,Prabaharan P,Auer JL,Sandiford S,Cascio F,Chowdhury M,Hind C,Wand ME,Sutton JM,Rahman KM

    更新日期：2017-08-01 00:00:00

  • Targeting the Warburg Effect in cancer; relationships for 2-arylpyridazinones as inhibitors of the key glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3).

    abstract：:High-throughput screening of a small-molecule library identified a 5-triazolo-2-arylpyridazinone as a novel inhibitor of the important glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3). Such inhibitors are of interest due to PFKFB3's control of the important glycolytic pathway used by cancer cel...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.12.041

    authors： Brooke DG,van Dam EM,Watts CK,Khoury A,Dziadek MA,Brooks H,Graham LJ,Flanagan JU,Denny WA

    更新日期：2014-02-01 00:00:00

  • Enzyme-catalysed enantioselective hydrolysis of racemic naproxen nitrile.

    abstract：:The bacterial strain Rhodococcus butanica (ATCC 21197), which exhibits nitrilase and nitrile hydratase/amidase activities, catalyses the enantioselective hydrolysis of racemic naproxen nitrile (R/S)-1 to furnish a moderate enantiomeric excess of (S)-naproxen (S)-3. Racemic naproxen amide (R/S)-2 is not a good substrat...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/0968-0896(94)85022-4

    authors： Effenberger F,Böhme J

    更新日期：1994-07-01 00:00:00