Discovery of a Novel Selective Dual Peroxisome Proliferator-Activated Receptor α/δ Agonist for the Treatment of Primary Biliary Cirrhosis.


:A novel peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist 5c was developed with an EC50 of 8 nM for PPARα, 5 nM for PPARδ, and >300-fold selectivity against PPARγ (EC50 = 2939 nM), respectively. Further ADME and pharmacokinetic studies indicated 5c possessed distinguished in vitro and in vivo profiles. The excellent in vivo efficacy of compound 5c was demonstrated by the rat primary biliary cirrhosis (PBC) model.


ACS Med Chem Lett


Jiang Z,Liu X,Yuan Z,He H,Wang J,Zhang X,Gong Z,Hou L,Shen L,Guo F,Zhang J,Wang J,Xu D,Liu Z,Li H,Chen X,Long C,Li J,Chen S




Has Abstract


2019-06-24 00:00:00










  • Discovery of 4,4-Disubstituted Quinazolin-2-ones as T-Type Calcium Channel Antagonists.

    abstract::A novel series of quinazolinone T-type calcium channel antagonists have been prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 by modifications of the 3- and 4-positions of the quinazolinone ring afforded potent and selective antagonists that displayed in vivo central nervou...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Barrow JC,Rittle KE,Reger TS,Yang ZQ,Bondiskey P,McGaughey GB,Bock MG,Hartman GD,Tang C,Ballard J,Kuo Y,Prueksaritanont T,Nuss CE,Doran SM,Fox SV,Garson SL,Kraus RL,Li Y,Marino MJ,Kuzmick Graufelds V,Uebele VN,R

    更新日期:2010-02-01 00:00:00

  • Discovery of INCB8761/PF-4136309, a Potent, Selective, and Orally Bioavailable CCR2 Antagonist.

    abstract::We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in v...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Xue CB,Wang A,Han Q,Zhang Y,Cao G,Feng H,Huang T,Zheng C,Xia M,Zhang K,Kong L,Glenn J,Anand R,Meloni D,Robinson DJ,Shao L,Storace L,Li M,Hughes RO,Devraj R,Morton PA,Rogier DJ,Covington M,Scherle P,Diamond

    更新日期:2011-10-05 00:00:00

  • Pharmacophore-Based Design of New Chemical Scaffolds as Translational Readthrough-Inducing Drugs (TRIDs).

    abstract::Translational readthrough-inducing drugs (TRIDs) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we repor...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tutone M,Pibiri I,Perriera R,Campofelice A,Culletta G,Melfi R,Pace A,Almerico AM,Lentini L

    更新日期:2020-02-18 00:00:00

  • Structure-Metabolism Relationships in the Glucuronidation of d-Amino Acid Oxidase Inhibitors.

    abstract::Representative d-amino acid oxidase (DAAO) inhibitors were subjected to in vitro liver microsomal stability tests in the absence or presence of uridine diphosphate glucuronic acid (UDPGA). While carboxylate-based DAAO inhibitors displayed little glucuronidation, most DAAO inhibitors containing α-hydroxycarbonyl moiety...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zimmermann SC,Rais R,Alt J,Burzynski C,Slusher BS,Tsukamoto T

    更新日期:2014-10-21 00:00:00

  • The Dark Side of Fluorine.

    abstract::Despite the perceived stability of the C-F bond, chemical instability and drug-metabolizing enzymes can lead to its cleavage. The resulting release of fluoride and formation of certain metabolites may cause safety issues and warrant the medicinal chemists' attention. ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 社论


    authors: Pan Y

    更新日期:2019-06-20 00:00:00

  • Evaluation of a Series of β-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads.

    abstract::Despite several years of research, only a handful of β-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Oehlrich D,Peschiulli A,Tresadern G,Van Gool M,Vega JA,De Lucas AI,Alonso de Diego SA,Prokopcova H,Austin N,Van Brandt S,Surkyn M,De Cleyn M,Vos A,Rombouts FJR,Macdonald G,Moechars D,Gijsen HJM,Trabanco AA

    更新日期:2019-07-02 00:00:00

  • Design, Synthesis, and Anti-HBV Activity of New Bis(l-amino acid) Ester Tenofovir Prodrugs.

    abstract::A series of bis(l-amino acid) ester prodrugs of tenofovir (TFV) were designed and synthesized as new anti-HBV agents in this work. Four compounds 11, 12a, 12d, and 13b displayed better anti-HBV activity (IC50: 0.71-4.22 μM) than the parent drug TFV. The most active compound 11 (IC50: 0.71 μM), a bis(l-valine) ester pr...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wang A,Wu S,Tao Z,Li X,Lv K,Ma C,Li Y,Li L,Liu M

    更新日期:2019-05-16 00:00:00

  • Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4).

    abstract::GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategi...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Brooks CA,Barton LS,Behm DJ,Eidam HS,Fox RM,Hammond M,Hoang TH,Holt DA,Hilfiker MA,Lawhorn BG,Patterson JR,Stoy P,Roethke TJ,Ye G,Zhao S,Thorneloe KS,Goodman KB,Cheung M

    更新日期:2019-07-15 00:00:00

  • Structures of human acetylcholinesterase bound to dihydrotanshinone I and territrem B show peripheral site flexibility.

    abstract::Acetylcholinesterase is a critical enzyme that regulates neurotransmission by degrading the neurotransmitter acetylcholine in synapses of the nervous system. It is an important target for both therapeutic drugs that treat Alzheimer's disease and chemical warfare agents that cripple the nervous system and cause death t...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Cheung J,Gary EN,Shiomi K,Rosenberry TL

    更新日期:2013-09-23 00:00:00

  • Discovery of G Protein-Biased EP2 Receptor Agonists.

    abstract::To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ogawa S,Watanabe T,Sugimoto I,Moriyuki K,Goto Y,Yamane S,Watanabe A,Tsuboi K,Kinoshita A,Kigoshi H,Tani K,Maruyama T

    更新日期:2016-01-04 00:00:00

  • 1,2,4-Triazolidine-3-thiones as Narrow Spectrum Antibiotics against Multidrug-Resistant Acinetobacter baumannii.

    abstract::With only two new classes of antibiotics developed in the last 40 years, novel antibiotics are desperately needed to combat the growing problem of multidrug-resistant and extensively drug resistant bacteria, particularly Gram-negative bacteria. Described in this letter is the synthesis and antibiotic activity of 1,2,4...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Huggins WM,Minrovic BM,Corey BW,Jacobs AC,Melander RJ,Sommer RD,Zurawski DV,Melander C

    更新日期:2016-11-12 00:00:00

  • Discovery and in Vitro Optimization of 3-Sulfamoylbenzamides as ROMK Inhibitors.

    abstract::Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Sammons MF,Kharade SV,Filipski KJ,Boehm M,Smith AC,Shavnya A,Fernando DP,Dowling MS,Carpino PA,Castle NA,Zellmer SG,Antonio BM,Gosset JR,Carlo A,Denton JS

    更新日期:2018-01-19 00:00:00

  • Small Molecule Lysyl Oxidase-like 2 (LOXL2) Inhibitors: The Identification of an Inhibitor Selective for LOXL2 over LOX.

    abstract::Two series of novel LOXL2 enzyme inhibitors are described: benzylamines substituted with electron withdrawing groups at the para-position and 2-substituted pyridine-4-ylmethanamines. The most potent compound, (2-chloropyridin-4-yl)methanamine 20 (hLOXL2 IC50 = 126 nM), was shown to be selective for LOXL2 over LOX and ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hutchinson JH,Rowbottom MW,Lonergan D,Darlington J,Prodanovich P,King CD,Evans JF,Bain G

    更新日期:2017-03-01 00:00:00

  • Synthesis and Optimization of Kv7 (KCNQ) Potassium Channel Agonists: The Role of Fluorines in Potency and Selectivity.

    abstract::Based on the potent Kv7 agonist RL-81, we prepared new lead structures with greatly improved selectivity for Kv7.2/Kv7.3 over related potassium channels, i.e., Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5. RL-36 and RL-12 maintain an agonist EC2x of ca. 1 μM on Kv7.2/Kv7.3 in a high-throughput assay on an automated electrophysio...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Liu R,Tzounopoulos T,Wipf P

    更新日期:2019-05-08 00:00:00

  • Design of Selective Benzoxazepin PI3Kδ Inhibitors Through Control of Dihedral Angles.

    abstract::A novel selective benzoxazepin inhibitor of PI3Kδ has been discovered. Beginning from compound 3, an αPI3K inhibitor, we utilized structure-based drug design and computational analysis of dihedral torsion angles to optimize for PI3Kδ isoform potency and isoform selectivity. Further medicinal chemistry optimization of ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Safina BS,Elliott RL,Forrest AK,Heald RA,Murray JM,Nonomiya J,Pang J,Salphati L,Seward EM,Staben ST,Ultsch M,Wei B,Yang W,Sutherlin DP

    更新日期:2017-08-25 00:00:00

  • N-Acylbenzenesulfonamide Dihydro-1,3,4-oxadiazole Hybrids: Seeking Selectivity toward Carbonic Anhydrase Isoforms.

    abstract::A series of N-acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids (EMAC8000a-m) was designed and synthesized with the aim to target tumor associated carbonic anhydrase (hCA) isoforms IX and XII. Most of the compounds were selective inhibitors of the tumor associated hCA XII. Moreover, resolution of EMAC8000d racem...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bianco G,Meleddu R,Distinto S,Cottiglia F,Gaspari M,Melis C,Corona A,Angius R,Angeli A,Taverna D,Alcaro S,Leitans J,Kazaks A,Tars K,Supuran CT,Maccioni E

    更新日期:2017-06-21 00:00:00

  • Identification of a New RXRα Antagonist Targeting the Coregulator-Binding Site.

    abstract::Retinoid X receptor-alpha (RXRα) is implicated in the regulation of many biological processes and also represents a unique intracellular target for pharmacologic interventions. Efforts on discovery of small molecules targeting RXRα have been primarily focused on the molecules that bind to its classical ligand-binding ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chen F,Liu J,Huang M,Hu M,Su Y,Zhang XK

    更新日期:2014-05-14 00:00:00

  • Cytosine-Based TET Enzyme Inhibitors.

    abstract::DNA methylation is known as the prima donna epigenetic mark for its critical role in regulating local gene transcription. Changes in the landscape of DNA methylation across the genome occur during cellular transition, such as differentiation and altered neuronal plasticity, and become dysregulated in disease states su...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chua GNL,Wassarman KL,Sun H,Alp JA,Jarczyk EI,Kuzio NJ,Bennett MJ,Malachowsky BG,Kruse M,Kennedy AJ

    更新日期:2019-01-31 00:00:00

  • Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA4 Hydrolase.

    abstract::Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA4 hydrolase (LTA4H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure-a...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hiesinger K,Schott A,Kramer JS,Blöcher R,Witt F,Wittmann SK,Steinhilber D,Pogoryelov D,Gerstmeier J,Werz O,Proschak E

    更新日期:2019-10-30 00:00:00

  • Benzoxaboroles: New Potent Inhibitors of the Carbonic Anhydrases of the Pathogenic Bacterium Vibrio cholerae.

    abstract::A series of urea/thiourea substituted benzoxaboroles was investigated for the inhibition of the three carbonic anhydrases encoded by Vibrio cholerae (VchCAα, VchCAβ, and VchCAγ). In particular, benzoxaborole derivatives were here first assayed for the inhibition of a γ-class CA, extending the panel of CA classes that ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Bonardi A,Nocentini A,Cadoni R,Del Prete S,Dumy P,Capasso C,Gratteri P,Supuran CT,Winum JY

    更新日期:2020-09-09 00:00:00

  • Visible-Light Photocatalysis as an Enabling Technology for Drug Discovery: A Paradigm Shift for Chemical Reactivity.

    abstract::Visible light-mediated photocatalysis, which relies on the ability of photocatalysts to absorb low-energy visible light and engage in single-electron transfer (SET) or energy transfer (ET) processes with organic substrates, has emerged as one of the fastest growing fields in organic synthesis. This catalytic platform ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Li P,Terrett JA,Zbieg JR

    更新日期:2020-09-21 00:00:00

  • Discovery of a novel broad-spectrum antifungal agent derived from albaconazole.

    abstract::Synthesis of a strict structural analogue of albaconazole in which the quinazolinone ring is fused by a thiazole moiety led to the discovery of a new triazole with broad-spectrum antifungal activity. Compound I exhibited high in vitro activity against pathogenic Candida species and filamentous fungi and showed prelimi...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Guillon R,Pagniez F,Picot C,Hédou D,Tonnerre A,Chosson E,Duflos M,Besson T,Logé C,Le Pape P

    更新日期:2013-01-17 00:00:00

  • Discovery of Highly Selective and Potent HDAC3 Inhibitors Based on a 2-Substituted Benzamide Zinc Binding Group.

    abstract::The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chemistry (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series containing 2-substitute...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Liu J,Yu Y,Kelly J,Sha D,Alhassan AB,Yu W,Maletic MM,Duffy JL,Klein DJ,Holloway MK,Carroll S,Howell BJ,Barnard RJO,Wolkenberg S,Kozlowski JA

    更新日期:2020-10-13 00:00:00

  • 2-Aminothiazole-4-carboxamides Enhance Readthrough of Premature Termination Codons by Aminoglycosides.

    abstract::Nonsense mutations introduce a premature termination codon (PTC) and are the underlying cause of multiple rare genetic diseases and cancers. Although certain aminoglycosides bind to eukaryotic ribosomes enabling incorporation of an amino acid at the PTC and formation of full-length protein, they are inefficient and to...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Rabea SM,Baradaran-Heravi A,Balgi AD,Krause A,Hosseini Farahabadi S,Roberge M,Grierson DS

    更新日期:2019-04-09 00:00:00

  • Novel N-Substituted Benzomorphan-Based Compounds: From MOR-Agonist/DOR-Antagonist to Biased/Unbiased MOR Agonists.

    abstract::Modifications at the basic nitrogen of the benzomorphan scaffold allowed the development of compounds able to segregate physiological responses downstream of the receptor signaling, opening new possibilities in opioid drug development. Alkylation of the phenyl ring in the N-substituent of the MOR-agonist/DOR-antagonis...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Pasquinucci L,Parenti C,Ruiz-Cantero MC,Georgoussi Z,Pallaki P,Cobos EJ,Amata E,Marrazzo A,Prezzavento O,Arena E,Dichiara M,Salerno L,Turnaturi R

    更新日期:2020-01-28 00:00:00

  • Maturing from embryonic to adult policy on stem cell therapeutics.

    abstract::The National Institutes of Health (NIH) closure of the agency's Center for Regenerative Medicine (CRM), which focused on therapeutic development of induced pluripotent stem cells (iPS), was caused by the lack of progress in practical development of the iPSs for use in human therapies. As the NIH evaluates priorities i...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Maguire G

    更新日期:2014-10-08 00:00:00

  • Multicomponent Synthesis and Biological Evaluation of a Piperazine-Based Dopamine Receptor Ligand Library.

    abstract::A series of 1,4-disubstituted piperazine-based compounds were designed, synthesized, and evaluated as dopamine D2/D3 receptor ligands. The synthesis relies on the key multicomponent split-Ugi reaction, assessing its great potential in generating chemical diversity around the piperazine core. With the aim of evaluating...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Stucchi M,Gmeiner P,Huebner H,Rainoldi G,Sacchetti A,Silvani A,Lesma G

    更新日期:2015-06-23 00:00:00

  • Kinetic profile of amyloid formation in the presence of an aromatic inhibitor by nuclear magnetic resonance.

    abstract::The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are p...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Liu G,Gaines JC,Robbins KJ,Lazo ND

    更新日期:2012-08-28 00:00:00

  • Epimers Switch Galectin-9 Domain Selectivity: 3N-Aryl Galactosides Bind the C-Terminal and Gulosides Bind the N-Terminal.

    abstract::A series of 3-deoxy-3-N-arylated-β-d-galactoside and -guloside derivatives have been synthesized by cesium fluoride/trimetylsilylaryl triflate-mediated benzyne generation and N-arylation of 3-deoxy-3-amino-β-d-galactosides and -gulosides, respectively. Evaluation as ligands to galectin-1, 2, 3, 4N (N-terminal domain),...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Mahanti M,Pal KB,Sundin AP,Leffler H,Nilsson UJ

    更新日期:2019-12-04 00:00:00

  • Discovery of New Acid Ceramidase-Targeted Acyclic 5-Alkynyl and 5-Heteroaryl Uracil Nucleosides.

    abstract::A series of novel N-acyclic uracil analogs with linear, branched, aromatic, and cyclopropyl-alkynyl as well as heteroaryl moieties at C-5 were prepared using palladium catalyzed Sonogashira and Stille cross-coupling and evaluated against malignant tumor cell lines. C-5-Furan-2-yl uracil derivative 6 was shown to be mo...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章


    authors: Meščić A,Harej A,Klobučar M,Glavač D,Cetina M,Pavelić SK,Raić-Malić S

    更新日期:2015-10-05 00:00:00