当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY LETTERS期刊下所有文献 > Increasing metabolic stability via the deuterium kinetic isotope effect: An example from a proline-amide-urea aminothiazole series of phosphatidylinositol-3 kinase alpha inhibitors.

Increasing metabolic stability via the deuterium kinetic isotope effect: An example from a proline-amide-urea aminothiazole series of phosphatidylinositol-3 kinase alpha inhibitors.

Abstract：

:In vitro metabolic identification studies with a PI3K-α inhibitor lead molecule 1 identified a single predominant site of oxidative metabolism to be occurring within a tert.butyl moiety. Modification of the tert.butyl group within the lead molecule 1, to the corresponding d9-tert.butyl analogue 2, led to an increase in both the in vitro and in vivo metabolic stability. This increase in metabolic stability resulted in a 2-fold increase in the oral bioavailability measured in the rat, and a 3-fold increase in potency in a chronic in vivo study in the mouse, for 2 when compared to 1.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Fairhurst RA,Caravatti G,Guagnano V,Aichholz R,Blanz J,Blasco F,Wipfli P,Fritsch C,Maira SM,Schnell C,Seiler FH

doi

10.1016/j.bmcl.2016.08.041

subject

Has Abstract

pub_date

2016-10-01 00:00:00

pages

4729-4734

issue

19

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(16)30862-9

journal_volume

26

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS文献大全
  • Synthesis of chimeric tetrapeptide-linked cholic acid derivatives: impending synergistic agents.

    abstract：:Tetrapeptides derived from glycine and beta-alanine were hooked at the C-3beta position of the modified cholic acid to realize novel linear tetrapeptide-linked cholic acid derivatives. All the synthesized compounds were tested against a wide variety of microorganisms (gram-negative bacteria, gram-positive bacteria and...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.09.013

    authors： Bavikar SN,Salunke DB,Hazra BG,Pore VS,Dodd RH,Thierry J,Shirazi F,Deshpande MV,Kadreppa S,Chattopadhyay S

    更新日期：2008-10-15 00:00:00

  • Synthesis and structure-activity relationships of CP-122,721, a second-generation NK-1 receptor antagonist.

    abstract：:The synthesis and SAR of benzylamine side chain analogs of the NK-1 receptor antagonist CP-99,994 are described. The 5-trifluoromethoxy analog, CP-122,721, shows superior in vivo blockade of NK-1 receptor mediated responses. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(98)00012-2

    authors： Rosen TJ,Coffman KJ,McLean S,Crawford RT,Bryce DK,Gohda Y,Tsuchiya M,Nagahisa A,Nakane M,Lowe JA 3rd

    更新日期：1998-02-03 00:00:00

  • Novel racemic tetrahydrocurcuminoid dihydropyrimidinone analogues as potent acetylcholinesterase inhibitors.

    abstract：:The synthesis of racemic tetrahydrocurcumin- (THC-), tetrahydrodemethoxycurcumin- (THDC-) and tetrahydrobisdemethoxycurcumin- (THBDC-) dihydropyrimidinone (DHPM) analogues was achieved by utilizing the multi-component Biginelli reaction in the presence of copper sulphate as a catalyst. The evaluation of acetylcholines...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.03.069

    authors： Arunkhamkaew S,Athipornchai A,Apiratikul N,Suksamrarn A,Ajavakom V

    更新日期：2013-05-15 00:00:00

  • Synthesis and insecticidal activity of new oxime derivatives of podophyllotoxin-based phenazines against Mythimna separata Walker.

    abstract：:To discover new natural-product-based insecticidal agents, a series of novel oxime derivatives of podophyllotoxin-based phenazines modified in the C, D and E rings of podophyllotoxin were prepared and tested as insecticidal agents against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2014.10.081

    authors： Zhi X,Yang C,Yu X,Xu H

    更新日期：2014-12-15 00:00:00

  • Enzymatic syntheses of 6-(4H-selenolo[3,2-b]pyrrolyl)-L-alanine, 4-(6H-selenolo[2,3-b]pyrrolyl)-L-alanine, and 6-(4H-furo[3,2-b]pyrrolyl-L-alanine.

    abstract：:6-(4H-Selenolo[3,2-b]pyrrolyl)-L-alanine 1, 4-(6H-selenolo[2,3-b]pyrrolyl)-L-alanine 2, and 6-(4H-furo[3,2-b]pyrrolyl)-L-alanine 3 have been synthesized via reactions of selenolo[3,2-b]pyrrole, selenolo[2,3-b]pyrrole, and furo[3,2-b]pyrrole, respectively, with L-serine. The reactions are catalyzed by Salmonella typhim...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(99)00067-0

    authors： Welch M,Phillips RS

    更新日期：1999-03-08 00:00:00

  • Imidazo[1,2-b][1,2,4]triazines as alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety.

    abstract：:Imidazo[1,2-a]pyrimidines and imidazo[1,2-b][1,2,4]triazines are ligands for the benzodiazepine binding site of GABA(A) receptors that are functionally selective for the alpha2/alpha3 subtypes over the alpha1 subtype. SAR studies to optimise this functional selectivity, pharmacokinetic and behavioural data are describ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2005.12.044

    authors： Jennings AS,Lewis RT,Russell MG,Hallett DJ,Street LJ,Castro JL,Atack JR,Cook SM,Lincoln R,Stanley J,Smith AJ,Reynolds DS,Sohal B,Pike A,Marshall GR,Wafford KA,Sheppard WF,Tye SJ

    更新日期：2006-03-15 00:00:00

  • Synthesis and antibacterial activity of 3-benzylamide derivatives as FtsZ inhibitors.

    abstract：:The emergence and spread of multidrug-resistant strains of the human pathological bacteria are generating a threat to public health worldwide. In the current study, a series of PC190723 derivatives was synthesized and investigated for their antimicrobial activity. The compounds exhibited good activity against several ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2017.02.032

    authors： Hu Z,Zhang S,Zhou W,Ma X,Xiang G

    更新日期：2017-04-15 00:00:00

  • Tricyclic sulfones as orally active gamma-secretase inhibitors: synthesis and structure-activity relationship studies.

    abstract：:Tricyclic sulfones were designed as gamma-secretase inhibitors and found to have excellent potency. Extensive SAR shows that a large number of sulfonamides at position 7 of the tricycle are very well tolerated. Compounds such as 15a and 15c showed remarkable in vivo potency. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.04.104

    authors： Sasikumar TK,Qiang L,Burnett DA,Cole D,Xu R,Li H,Greenlee WJ,Clader J,Zhang L,Hyde L

    更新日期：2010-06-15 00:00:00

  • Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKβ inhibitors.

    abstract：:Inactivation of the NF-κB signaling pathway by inhibition of IKKβ is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKβ inhibitor, SPC-839, and then biologically evaluated. The resulting ana...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2014.04.058

    authors： Park CH,Lee C,Yang JS,Joe BY,Chun K,Kim H,Kim HY,Kang JS,Lee JI,Kim MH,Han G

    更新日期：2014-06-15 00:00:00

  • pH-Dependant fluorescence switching of an i-motif structure incorporating an isomeric azobenzene/pyrene fluorophore.

    abstract：:In this study, we synthesized an Azo-py phosphoramidite, featuring azobenzene and pyrene units, as a novel fluorescent and isomeric (trans- and cis-azobenzene units) material, which we incorporated in an i-motif DNA sequence. We then monitored the structural dynamics and changes in fluorescence as the modified DNA seq...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2017.04.015

    authors： Joo HN,Van Thi Nguyen T,Chae HK,Seo YJ

    更新日期：2017-06-01 00:00:00

  • Squalene-derived flexible linkers for bioactive peptides.

    abstract：:A regiochemical and stereochemical mixture of flexible linkers bearing terminal azide functionality was synthesized in two steps from squalene and was used to connect two high affinity NDP-alpha-MSH ligands or two low affinity MSH(4) ligands. The ligands were N-terminally acylated using N-hydroxysuccinimidoyl 5-hexyno...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2007.04.001

    authors： Jagadish B,Sankaranarayanan R,Xu L,Richards R,Vagner J,Hruby VJ,Gillies RJ,Mash EA

    更新日期：2007-06-15 00:00:00

  • Syntheses and antifilarial profile of 7-chloro-4-(substituted amino) quinolines: a new class of antifilarial agents.

    abstract：:The syntheses of 7-chloro-4-(substituted amino) quinolines (2-22) and their antifilarial activities are delineated. Some of the screened compounds have shown promising filarial response and sterilization effect on female Acanthocheilonema viteae in rodents. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(00)00255-9

    authors： Tewari S,Chauhan PM,Bhaduri AP,Fatima N,Chatterjee RK

    更新日期：2000-07-03 00:00:00

  • LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs.

    abstract：:The transporter protein Large-neutral Amino Acid Transporter 1 (LAT-1, SLC7A5) is responsible for transporting amino acids such as tyrosine and phenylalanine as well as thyroid hormones, and it has been exploited as a drug delivery mechanism. Recently its role in cancer has become increasingly appreciated, as it has b...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2016.04.023

    authors： Augustyn E,Finke K,Zur AA,Hansen L,Heeren N,Chien HC,Lin L,Giacomini KM,Colas C,Schlessinger A,Thomas AA

    更新日期：2016-06-01 00:00:00

  • Novel bis-arylsulfonamides and aryl sulfonimides as inactivators of plasminogen activator inhibitor-1 (PAI-1).

    abstract：:Inactivators of plasminogen activator inhibitor-1 (PAI-1) have been identified as possible treatments for a range of conditions, including atherosclerosis, venous thrombosis, and obesity. We describe the synthesis and inhibitory activity of a novel series of compounds based on bis-arylsulfonamide and aryl sulfonimide ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.12.051

    authors： El-Ayache NC,Li SH,Warnock M,Lawrence DA,Emal CD

    更新日期：2010-02-01 00:00:00

  • Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas.

    abstract：:We report the discovery of a novel, chiral azetidine urea inhibitor of Fatty Acid Amide Hydrolase (FAAH,) and describe the surprising species selectivity of VER-156084 versus rat and human FAAH and also hCB1. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.05.097

    authors： Hart T,Macias AT,Benwell K,Brooks T,D'Alessandro J,Dokurno P,Francis G,Gibbons B,Haymes T,Kennett G,Lightowler S,Mansell H,Matassova N,Misra A,Padfield A,Parsons R,Pratt R,Robertson A,Walls S,Wong M,Roughley S

    更新日期：2009-08-01 00:00:00

  • Synthesis and biological evaluation of some novel thiazole substituted benzotriazole derivatives.

    abstract：:A series of novel hybrid molecules 4a-y containing thiazole and benzotriazole templates were designed and synthesized. The structures of the synthesized compounds were elucidated by IR, (1)H NMR, (13)C NMR and mass spectral data. All the synthesized compounds were tested for their antimicrobial activity (zone of inhib...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2012.03.094

    authors： Gaikwad ND,Patil SV,Bobade VD

    更新日期：2012-05-15 00:00:00

  • Ejection of structural zinc leads to inhibition of γ-butyrobetaine hydroxylase.

    abstract：:γ-Butyrobetaine hydroxylase (BBOX) is a 2-oxoglutarate and Fe(II) dependent oxygenase that catalyses an essential step during carnitine biosynthesis in animals. BBOX is inhibited by ejection of structural zinc by a set of selenium containing analogues. Previous structural analyses indicated that an undisrupted N-termi...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2014.09.035

    authors： Rydzik AM,Brem J,Struwe WB,Kochan GT,Benesch JL,Schofield CJ

    更新日期：2014-11-01 00:00:00

  • Synthesis of the new pseudo-symmetrical tamoxifen derivatives and their anti-tumor activity.

    abstract：:Three new pseudo-symmetrical tamoxifen derivatives, RID-B (15), C (16), and D (17), were synthesized via the novel three-component coupling reaction, and the structure-activity relationships of the pseudo-symmetrical tamoxifen derivatives were examined. It was discovered that 15 strongly inhibits the viability of HL-6...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2007.02.037

    authors： Shiina I,Sano Y,Nakata K,Kikuchi T,Sasaki A,Ikekita M,Hasome Y

    更新日期：2007-05-01 00:00:00

  • Synthesis, antibacterial and antifungal activities of some carbazole derivatives.

    abstract：:A series of N-substituted carbazole derivatives were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Bacillus proteus, Candida albicans and Aspergillus f...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.01.159

    authors： Zhang FF,Gan LL,Zhou CH

    更新日期：2010-03-15 00:00:00

  • Preparation of L-alpha-phosphatidyl-D-myo-inositol 3-phosphate (3-PIP) and 3,5-bisphosphate (3,5-PIP2).

    abstract：:Practical, asymmetric total syntheses of the title phospholipids from a readily available myo-inositol derivative as well as short chain and cross-linkable aminoether analogues are described. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(00)00315-2

    authors： Falck JR,Krishna UM,Capdevila JH

    更新日期：2000-08-07 00:00:00

  • Synthesis and biological properties of new 1beta-methylcarbapenems containing heteroaromatic thioether moiety.

    abstract：:The synthesis and biological activities of a series of new 1beta-methylcarbapenems 1a-h having heteroaromatic thioether moiety at C-5 position of pyrrolidine were described. Among these compounds, 1,2,3-thiadiazole derivative 1h showed the most potent antibacterial activity and advanced pharmacokinetics in comparison ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(01)00451-6

    authors： Shin KJ,Koo KD,Yoo KH,Kang YK,Park SW,Kim DJ

    更新日期：2001-09-03 00:00:00

  • Synthesis and PGE₂ production inhibition of s-triazine derivatives as a novel scaffold in RAW 264.7 macrophage cells.

    abstract：:We present the synthesis and biological evaluation of a collection of s-triazine derivatives as a novel scaffold of compounds with the capability to inhibit the PGE₂ production in LPS-induced RAW 264.7 macrophage cells. A total of 12 derivatives were synthesized and assayed for PGE₂ reduction at 10 μM concentration. T...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2014.10.031

    authors： Kang SM,Lee J,Jin JH,Kim M,Lee S,Lee HH,Shin JS,Lee KT,Lee JY

    更新日期：2014-12-01 00:00:00

  • Design of new inhibitors for cdc2 kinase based on a multiple pseudosubstrate structure.

    abstract：:New inhibitors have been designed for cdc2 kinase based on a multiple pseudosubstrate structure. The new inhibitors have three different structural components: 3,4-bis(indol-3-yl)maleimide, Ac-Cys-(Ser)-Pro-Lys-Lys-NHMe, and ethyloxy group between the two components. Inhibitory activities toward cdc2 and other protein...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(98)00163-2

    authors： Sasaki S,Hashimoto T,Obana N,Yasuda H,Uehara Y,Maeda M

    更新日期：1998-05-05 00:00:00

  • Chlorin e6-cholesterol conjugate and its copper complex. Simple synthesis and entrapping in phospholipid vesicles.

    abstract：:Synthesis of 13'[(cholest-5-en)-3beta-yloxyethoxycarbamoyl]-chlorin e6 starting from methylpheophorbide and 3beta(2-hydroxy)-ethoxycholest-5-ene is presented, as well as the preparation of related copper complex. Both conjugates obtained may be simply incorporated in phosphatidyl choline vesicles. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.03.041

    authors： Nikolaeva IA,Misharin AY,Ponomarev GV,Timofeev VP,Tkachev YV

    更新日期：2010-05-01 00:00:00

  • Structure-based design of novel human Pin1 inhibitors (III): optimizing affinity beyond the phosphate recognition pocket.

    abstract：:The design of potent Pin1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based Pin1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been prev...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2014.07.044

    authors： Guo C,Hou X,Dong L,Marakovits J,Greasley S,Dagostino E,Ferre R,Johnson MC,Humphries PS,Li H,Paderes GD,Piraino J,Kraynov E,Murray BW

    更新日期：2014-09-01 00:00:00

  • Production of aminoglycosides in non-aminoglycoside producing Streptomyces lividans TK24.

    abstract：:The pRBM4 cosmid, which harbors a putative cluster of genes spanning a 31.8-kb chromosomal region of the ribostamycin producer Streptomyces ribosidificus ATCC 21294, was heterologously expressed in Streptomyces lividans TK24. ESI-MS/MS, HPLC, and LC-ESI MS analyses showed that the transformation gave rise to ribostamy...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2007.01.035

    authors： Subba B,Kurumbang NP,Jung YS,Yoon YJ,Lee HC,Liou K,Sohng JK

    更新日期：2007-04-01 00:00:00

  • Novel imidazolopyrimidines as dual PI3-Kinase/mTOR inhibitors.

    abstract：:This article describes the syntheses and SAR of a series of imidazolopyrimidine derivatives, which are evaluated as inhibitors of PI3-Kinase (PI3K) and mTOR. These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.11.057

    authors： Venkatesan AM,Dehnhardt CM,Chen Z,Santos ED,Dos Santos O,Bursavich M,Gilbert AM,Ellingboe JW,Ayral-Kaloustian S,Khafizova G,Brooijmans N,Mallon R,Hollander I,Feldberg L,Lucas J,Yu K,Gibbons J,Abraham R,Mansour TS

    更新日期：2010-01-15 00:00:00

  • Design and synthesis of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles as androgen receptor antagonists.

    abstract：:A novel series of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles has been synthesized. The ability of these compounds to act as antagonists of the androgen receptor was investigated and several were found to have potent activity in vitro and in vivo. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.06.034

    authors： Xiao HY,Balog A,Attar RM,Fairfax D,Fleming LB,Holst CL,Martin GS,Rossiter LM,Chen J,Cvjic ME,Dell-John J,Geng J,Gottardis MM,Han WC,Nation A,Obermeier M,Rizzo CA,Schweizer L,Spires T Jr,Shan W,Gavai A,Salvati ME

    更新日期：2010-08-01 00:00:00

  • Synthesis and evaluation of 6-hydroxy-7-methoxy-4-chromanone- and chroman-2-carboxamides as antioxidants.

    abstract：:A series of 6-hydroxy-7-methoxy-4-chromanone- (2a-e) and chroman-2-carboxamides (3a-e) were synthesized and their antioxidant activities were evaluated. While compounds 2a-e were less active, compounds 3a-e exhibited more potent inhibition of lipid peroxidation initiated by Fe(2+) and ascorbic acid in rat brain homoge...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2005.03.118

    authors： Lee H,Lee K,Jung JK,Cho J,Theodorakis EA

    更新日期：2005-06-02 00:00:00

  • Amides of xanthurenic acid as zinc-dependent inhibitors of Lp-PLA(2).

    abstract：:AX10185, the phenyl amide of xanthurenic acid, was found to be a sub-100nM inhibitor of Lp-PLA(2). However, in the presence of EDTA the inhibitory activity of AX10185 was extinguished while the enzymatic activity of Lp-PLA(2) did not change. Subsequent metal screening experiments determined the inhibition to be Zn(2+)...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.12.045

    authors： Lin EC,Hu Y,Amantea CM,Pham LM,Cajica J,Okerberg E,Brown HE,Fraser A,Du L,Kohno Y,Ishiyama J,Kozarich JW,Shreder KR

    更新日期：2012-01-15 00:00:00