Decreasing the CYP2D6 contribution to metabolism of a CK1ε inhibitor.

Abstract:

:Our internal casein kinase 1ε lead inhibitor, compound 1 was partially cleared by the polymorphic cytochrome P450 2D6. CYP2D6 involvement in metabolism implies more extensive clinical trials. We therefore wanted to reduce the contribution to clearance by this enzyme. We utilized metabolism reports for compound 1 performed in recombinant CYP2D6 together with structure-metabolism variation in structures of closely related analogs in order to see if we could incorporate similar substitution patterns in our lead compound. In addition, we utilized a previously established docking method using a modified CYP2D6 crystal structure to see if the metabolism patterns in CYP2D6 could be reproduced to afford the metabolites in the metabolism reports as well as those for the compounds used in the structure-metabolism relationship. All three of these steps, the metabolism report, the establishment of structure-metabolism relationships and the docking, lead to compound 10 where CYP2D6 was not involved in the clearance pathways.

journal_name

Bioorg Med Chem Lett

authors

Vaz RJ,Li Y,Metz M,Yang D,Shen H,Munson M

doi

10.1016/j.bmcl.2018.10.031

subject

Has Abstract

pub_date

2018-12-15 00:00:00

pages

3681-3684

issue

23-24

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(18)30833-3

journal_volume

28

pub_type

杂志文章
  • Design and syntheses of melanocortin subtype-4 receptor agonists: evolution of the pyridazinone archetype.

    abstract::The discovery and optimization of a new class of non-peptidyl, pyridazinone derived melanocortin subtype-4 receptor agonists is disclosed. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2003.09.026

    authors: Ujjainwalla F,Warner D,Walsh TF,Wyvratt MJ,Zhou C,Yang L,Kalyani RN,MacNeil T,Van der Ploeg LH,Rosenblum CI,Tang R,Vongs A,Weinberg DH,Goulet MT

    更新日期:2003-12-15 00:00:00

  • Discovery of 3-(2-aminoethyl)-5-(3-phenyl-propylidene)-thiazolidine-2,4-dione as a dual inhibitor of the Raf/MEK/ERK and the PI3K/Akt signaling pathways.

    abstract::A thiazolidine-2,4-dione derivative, 3-(2-aminoethyl)-5-(3-phenyl-propylidene)-thiazolidine-2,4-dione (2), was identified as a dual inhibitor of the Raf/MEK/ extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascades. The discovered compound inhibited cell prolifera...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.06.030

    authors: Li Q,Wu J,Zheng H,Liu K,Guo TL,Liu Y,Eblen ST,Grant S,Zhang S

    更新日期:2010-08-01 00:00:00

  • Effects of positional and geometrical isomerism on the biological activity of some novel oxazolidinones.

    abstract::Some novel oxazolidinone derivatives with benzotriazole as pendant have been synthesized and tested for antibacterial activity. Linearly attached benzotriazole derivative showed more potency compared to angular one in vitro. Out of E/Z-isomers of angularly attached derivatives E-isomer was found to be more potent than...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2004.10.073

    authors: Das J,Rao CV,Sastry TV,Roshaiah M,Sankar PG,Khadeer A,Kumar MS,Mallik A,Selvakumar N,Iqbal J,Trehan S

    更新日期:2005-01-17 00:00:00

  • Ethynylphenyl carbonates and carbamates as dual-action acetylcholinesterase inhibitors and anti-inflammatory agents.

    abstract::Novel ethynylphenyl carbonates and carbamates containing carbon- and silicon-based choline mimics were synthesized from their respective phenol and aniline precursors and screened for anticholinesterase and anti-inflammatory activities. All molecules were micromolar inhibitors of acetylcholinesterase (AChE), with IC50...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2015.10.039

    authors: Saxena J,Meloni D,Huang MT,Heck DE,Laskin JD,Heindel ND,Young SC

    更新日期:2015-12-01 00:00:00

  • Pharmacophore modeling and in silico screening for new KDR kinase inhibitors.

    abstract::In order to elucidate the essential structural features for KDR kinase inhibitors, three-dimensional pharmacophore hypotheses were built on the basis of a set of known KDR kinase inhibitors selected from the literature with CATALYST program. Several methods tools used in validation of pharmacophore hypothsis were pres...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2007.01.089

    authors: Yu H,Wang Z,Zhang L,Zhang J,Huang Q

    更新日期:2007-04-15 00:00:00

  • Synthesis and biological activity of trans-2,3-dihydroraloxifene.

    abstract::The synthesis and biological evaluation of trans-2,3-dihydroraloxifene, 2, is described. The synthesis proceeds in 8 steps in 20% overall yield. Relative trans 2,3-stereochemistry is definitively established in ester 6, which is converted to the title compound via derivatization, Grignard addition, and deprotection. E...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(99)00145-6

    authors: Schmid CR,Glasebrook AL,Misner JW,Stephenson GA

    更新日期:1999-04-19 00:00:00

  • Dual M3 antagonists-PDE4 inhibitors. Part 2: Synthesis and SAR of 3-substituted azetidinyl derivatives.

    abstract::Introduction of 3-substituted azetidinyl substituents onto the 4,6-diaminopyrimidine scaffold allowed the improvement of PDE4 inhibiting activities. Preliminary in vivo activity in pulmonary inflammation models is reported. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2007.03.047

    authors: Provins L,Christophe B,Danhaive P,Dulieu J,Gillard M,Quéré L,Stebbins K

    更新日期:2007-06-01 00:00:00

  • Flavonoids from Woodfordia fruticosa as potential SmltD inhibitors in the alternative biosynthetic pathway of peptidoglycan.

    abstract::SmltD is an ATP-dependent ligase that catalyzes the condensation of UDP-MurNAc-l-Ala and l-Glu to form UDP-MurNAc-l-Ala-l-Glu, in the newly discovered peptidoglycan biosynthesis pathway of a Gram-negative multiple-drug-resistant pathogen, Stenotrophomonas maltophilia. Phytochemical investigation of the 70% ethanol ext...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2021.127787

    authors: Lee YE,Kodama T,Win NN,Ki DW,Hoang NN,Wong CP,Lae KZW,Ngwe H,Dairi T,Morita H

    更新日期:2021-01-15 00:00:00

  • Synthesis and antifungal activity of the 2,2,5-tetrahydrofuran regioisomers of SCH 51048.

    abstract::The four 2,2,5-regioisomer counterparts of SCH 51048 were synthesized and evaluated. As with the parent series, only the two cis isomers possessed any in vitro activity, and only the activity of the isomer with the R-configuration at the tetrahydrofuran 2-carbon was significant. The activity data suggests that oxygen ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(02)00282-2

    authors: Lovey RG,Saksena AK,Girijavallabhan VM,Blundell P,Guzik H,Loebenberg D,Parmegiani RM,Cacciapuoti A

    更新日期:2002-07-08 00:00:00

  • 3-heterocyclyl quinolone inhibitors of the HCV NS5B polymerase.

    abstract::The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key anal...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2011.11.013

    authors: Kumar DV,Rai R,Brameld KA,Riggs J,Somoza JR,Rajagopalan R,Janc JW,Xia YM,Ton TL,Hu H,Lehoux I,Ho JD,Young WB,Hart B,Green MJ

    更新日期:2012-01-01 00:00:00

  • Bioactive terpenoids from Silybum marianum and their suppression on NO release in LPS-induced BV-2 cells and interaction with iNOS.

    abstract::Three new (1-3) and one known (4) bioactive terpenoids were isolated from the seeds of Silybum marianum based on the investigation to get new NO inhibitors. Their structures were determined by extensive NMR (1D and 2D NMR) and MS spectroscopic data, and the absolute configurations were identified by experimental and c...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2017.03.058

    authors: Qin NB,Li SG,Yang XY,Gong C,Zhang XY,Wang J,Li DH,Guo YQ,Li ZL,Hua HM

    更新日期:2017-05-15 00:00:00

  • Reaction of thiols with 7-methylbenzopentathiepin.

    abstract::Polysulfides typically react readily with thiols, thus, reactions of endogenous cellular thiols with the polysulfide linkage in naturally-occuring pentathiepin cytotoxins are likely to be an important aspect of their biological chemistry. Here, it is reported that the reaction of thiols with the pentathiepin ring syst...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(03)00103-3

    authors: Chatterji T,Gates KS

    更新日期:2003-04-07 00:00:00

  • N-alkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides, micro and delta opioid agonists: a micro address.

    abstract::The tertiary amide delta opioid agonist 2 is a potent antinociceptive agent. Compound 2 was metabolized in vitro and in vivo to secondary amide 3, a potent and selective micro opioid agonist. The SAR of a series of N-alkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides was examined. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2004.02.052

    authors: Carson JR,Coats SJ,Codd EE,Dax SL,Lee J,Martinez RP,McKown LA,Anne Neilson L,Pitis PM,Wu WN,Zhang SP

    更新日期:2004-05-03 00:00:00

  • Synthesis and evaluation of potent pyrrolidine H(3) antagonists.

    abstract::The synthesis and biological evaluation of novel antagonists of the rat H(3) receptor are described. These compounds differ from prototypical H(3) antagonists in that they do not contain an imidazole moiety, but rather a substituted aminopyrrolidine moiety. A systematic modification of the substituents on the aminopyr...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(02)00685-6

    authors: Vasudevan A,Conner SE,Gentles RG,Faghih R,Liu H,Dwight W,Ireland L,Kang CH,Esbenshade TA,Bennani YL,Hancock AA

    更新日期:2002-11-04 00:00:00

  • A new lateral root growth inhibitor from the sponge-derived fungus Aspergillus sp. LS45.

    abstract::Two new γ-lactones, aspergilactones A (1) and B (2), were discovered along with two known compounds, annularin A (3) and pericoterpenoid A (4), from a culture of the sponge-associated fungus Aspergillus sp. LS45. The planar structures of 1-4 were characterized using comprehensive spectroscopic methods and comparison w...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2019.04.051

    authors: Huang L,Ding L,Li X,Wang N,Yan Y,Yang M,Cui W,Benjamin Naman C,Cheng K,Zhang W,Zhang B,Jin H,He S

    更新日期:2019-07-01 00:00:00

  • Design, synthesis and antitumor activity of a novel PEG-A6-conjugated irinotecan derivative.

    abstract::A novel PEG-A6-conjugated irinotecan derivative 8 was designed and synthesized as antitumor agent by the PEGylation and A6-peptide modification of irinotecan. In vivo antitumor activity screening assay revealed that 8 exhibited better in vivo antiproliferation activity than irinotecan and its previous PEG-cRGD-conjuga...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2019.126847

    authors: Huang YQ,Yuan JD,Ding HF,Song YS,Qian G,Wang JL,Ji M,Zhang Y

    更新日期:2020-01-15 00:00:00

  • Parallel synthesis of acylsemicarbazide libraries: preparation of potent cyclin dependent kinase (cdk) inhibitors.

    abstract::Potent cyclin dependent kinase inhibitors were prepared using parallel synthesis methodology. Treating advanced intermediate 2 with a variety of hydrazides in DMSO at 80 degrees C for 30 min gave the desired acylsemicarbazides in good to excellent yield. Several compounds were active against cdk4/D1 and cdk2/E in the ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2004.09.023

    authors: Nugiel DA,Vidwans A,Dzierba CD

    更新日期:2004-11-15 00:00:00

  • The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian alpha-carbonic anhydrase isoforms.

    abstract::The protein tyrosine kinases (PTKs) are essential enzymes in cellular signaling processes that regulate cell growth, differentiation, migration and metabolism. Their inhibition was recently shown to constitute a new modality for treating cancers. Two clinically used PTK inhibitors (PTKIs), imatinib (Glivec/Gleevec) an...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2009.06.002

    authors: Parkkila S,Innocenti A,Kallio H,Hilvo M,Scozzafava A,Supuran CT

    更新日期:2009-08-01 00:00:00

  • A novel series of metabotropic glutamate receptor 5 negative allosteric modulators based on a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine core.

    abstract::A series of potent non-acetylinic negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5 NAMs) was developed starting from HTS screening hit 1. Potency was improved via iterative SAR, and physicochemical properties were optimized to deliver orally bioavailable compounds acceptable for in vivo t...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2013.06.044

    authors: Duvey G,Perry B,Le Poul E,Poli S,Bonnet B,Lambeng N,Charvin D,Donovan-Rodrigues T,Haddouk H,Gagliardi S,Rocher JP

    更新日期:2013-08-15 00:00:00

  • Novel and potent transforming growth factor beta type I receptor kinase domain inhibitor: 7-amino 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolines.

    abstract::A novel series of 7-amino 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolines was synthesized and their TbetaR-1 inhibitory, p38 MAPK inhibitory, and TbetaR-1-dependent cellular activity were evaluated. Compound 5a was found to be a highly potent in the enzyme assay and TbetaR-1-dependent cellular ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2004.04.065

    authors: Li HY,Wang Y,Yan L,Campbell RM,Anderson BD,Wagner JR,Yingling JM

    更新日期:2004-07-05 00:00:00

  • Synthesis and evaluation of a cyclic imine derivative conjugated to a fluorescent molecule for labeling of proteins.

    abstract::A cyclic imine conjugated to a fluorescent dansyl group was synthesized and used for covalent labeling of proteins. The covalent attachment to proteins was confirmed by gel electrophoresis and mass analysis. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2008.12.071

    authors: Guo HM,Minakawa M,Ueno L,Tanaka F

    更新日期:2009-02-15 00:00:00

  • Identification of urine metabolites of TFAP, a cyclooxygenase-1 inhibitor.

    abstract::Only a few COX-1-selective inhibitors are currently available, and the research on COX-1 selective inhibitors is not fully developed. The authors have produced several COX-1 selective inhibitors including N-(5-amino-2-pyridinyl)-4-trifluoromethylbenzamide: TFAP (3). Although 3 shows potent analgesic effect without gas...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2010.01.161

    authors: Kakuta H,Fukai R,Xiaoxia Z,Ohsawa F,Bamba T,Hirata K,Tai A

    更新日期:2010-03-15 00:00:00

  • Design, synthesis and biological evaluation of novel pyrazolo-pyrimidinones as DPP-IV inhibitors in diabetes.

    abstract::We report the design, synthesis, biological activity and docking studies of series of novel pyrazolo[3,4-d]pyrimidinones as DPP-IV inhibitors in diabetes. Molecules were synthesized and evaluated for their DPP-IV inhibition activity. Compounds 5e, 5k, 5o and 6a were found to be potent inhibitors of DPP-IV enzyme. Amon...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2015.09.015

    authors: Sagar SR,Agarwal JK,Pandya DH,Dash RP,Nivsarkar M,Vasu KK

    更新日期:2015-10-15 00:00:00

  • Design, synthesis and enzymatic evaluation of 3-O-substituted aryl β-D-galactopyranosides as inhibitors of Trypanosoma cruzi trans-sialidase.

    abstract::The trans-sialidase of Trypanosoma cruzi (TcTS) is a surface enzyme that modifies the parasite glycocalyx covering it with sialic acid. This process is essential to adhesion and invasion mechanisms in life cycle of the protozoan in the human host, making TcTS a very attractive molecular target for drug design. Using t...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2014.07.088

    authors: Silva BL,S Filho JD,Andrade P,Carvalho I,Alves RJ

    更新日期:2014-09-15 00:00:00

  • Cu2+-labeled dansyl compounds as fluorescent and PET probes for imaging apoptosis.

    abstract::Compound DNSTT-Cu2+, a novel chelate of Cu2+ with DOTA conjugated to a fluorescent dansyl fragment, is developed for imaging cell apoptosis. Apoptotic U-87MG cells could be selectively visualized by the fluorescence of DNSTT-Cu2+ from cytoplasm of cells, confirmed by the fluorescence of apoptosis cells co-labeled with...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2016.09.057

    authors: Han J,Wang X,Yu M

    更新日期:2016-11-15 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

  • Synthesis and antiplatelet activity of gemfibrozil chiral analogues.

    abstract::The chiral analogues of gemfibrozil 5-(2,5-dimethylphenoxy)-2-methylpentanoic acid and 5-(2,5-dimethylphenoxy)-2-ethylpentanoic acid were synthesized in optically active form using (S)-4-(1-methylethyl)-2-oxazolidinone as chiral auxiliary. All compounds inhibit human platelet aggregation. From these data, one can surm...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/s0960-894x(02)00021-5

    authors: Ammazzalorso A,Amoroso R,Baraldi M,Bettoni G,Braghiroli D,De Filippis B,Duranti A,Moretti M,Tortorella P,Tricca ML,Vezzalini F

    更新日期:2002-03-11 00:00:00

  • Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition.

    abstract::Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2008.03.050

    authors: Fish PV,Deur C,Gan X,Greene K,Hoople D,Mackenny M,Para KS,Reeves K,Ryckmans T,Stiff C,Stobie A,Wakenhut F,Whitlock GA

    更新日期:2008-04-15 00:00:00

  • Cardioprotective potential of N,α-L-rhamnopyranosyl vincosamide, an indole alkaloid, isolated from the leaves of Moringa oleifera in isoproterenol induced cardiotoxic rats: in vivo and in vitro studies.

    abstract::Hitherto unknown protective effect of N,α-L-rhamnopyranosyl vincosamide (VR), isolated from Moringa oleifera leaves in isoproterenol (ISO)-induced cardiac toxicity was evaluated in rats. Oral administration of VR at 40 mg/kg for 7 days markedly reduced the ISO-induced increase in the levels of serum cardiac markers su...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2012.12.060

    authors: Panda S,Kar A,Sharma P,Sharma A

    更新日期:2013-02-15 00:00:00

  • Synthesis, antitumor activity and mechanism of action of novel 1,3-thiazole derivatives containing hydrazide-hydrazone and carboxamide moiety.

    abstract::A series of novel 2,4,5-trisubstituted 1,3-thiazole derivatives containing hydrazide-hydrazine, and carboxamide moiety including 46 compounds T were synthesized, and evaluated for their antitumor activity in vitro against a panel of five human cancer cell lines. Eighteen title compounds T displayed higher inhibitory a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1016/j.bmcl.2016.05.059

    authors: He H,Wang X,Shi L,Yin W,Yang Z,He H,Liang Y

    更新日期:2016-07-15 00:00:00