当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing Thiophen-2-ylpropanoic Acid Scaffold.

Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing Thiophen-2-ylpropanoic Acid Scaffold.

Abstract：

:The free fatty acid receptor GPR40 is predominantly expressed in pancreatic β-cells and enhances insulin secretion in a glucose dependent manner. Therefore, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia for the treatment of type 2 diabetes mellitus (T2DM). Chemically and structurally diverse GPR40 agonists with high safety are pursued for the clinical development of GPR40-based pharmacotherapeutics. Herein we report our design and discovery of a new chemotype of GPR40 agonists free of the typical phenylpropanoic acid scaffold. The thiophen-2-ylpropanoic acid containing GPR40 modulators functioned as full agonists with high-efficacy response (Emax) and reduced lipophilicity. Significantly, the lead compound in this series, (R)-7k, exhibited more potent in vitro glucose-stimulated insulin secretion and in vivo glucose-lowering effects (10 mg/kg, po) than the GPR40 partial agonist TAK-875, which was once in phase III clinical trials, and high selectivity over the relevant receptors GPR120 and PPARγ.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Li H,Huang Q,Chen C,Xu B,Wang HY,Long YQ

doi

10.1021/acs.jmedchem.6b01357

subject

Has Abstract

pub_date

2017-04-13 00:00:00

pages

2697-2717

issue

7

eissn

0022-2623

issn

1520-4804

journal_volume

60

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Challenges in the Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

    abstract：:Since the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) as an attractive target for anticancer therapy in 2003, the search for inhibitors has been intensely pursued both in academia and in pharmaceutical companies. Many novel IDO1 inhibitor scaffolds have been described, and a few potent compounds have entered cli...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1021/acs.jmedchem.5b00326

    authors： Röhrig UF,Majjigapu SR,Vogel P,Zoete V,Michielin O

    更新日期：2015-12-24 00:00:00

  • (E)-3-[[[[6-(2-carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]-methyl]thio]methyl]benzoic acid and related compounds: high affinity leukotriene B4 receptor antagonists.

    abstract：:(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic acid (11, SB 201993) is a novel, potent LTB4 receptor antagonist. Compound 11 arose from a structure-activity study of a series of trisubstituted pyridines that demonstrated LTB4 receptor antagonist activity. The p...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00046a017

    authors： Daines RA,Chambers PA,Eggleston DS,Foley JJ,Griswold DE,Haltiwanger RC,Jakas DR,Kingsbury WD,Martin LD,Pendrak I

    更新日期：1994-09-30 00:00:00

  • 6,7-Dichloro-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline . A structurally novel beta-adrenergic receptor blocking agent.

    abstract：:Replacement of the catecholic hydroxyl groups of the beta-adrenergic receptor agonist 6,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline (trimetoquinol) with chloro substituents results in a compound with marked beta-adrenoceptor antagonist properties. This, therefore, parallels the similar transf...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00161a039

    authors： Kaiser C,Oh HJ,Garcia-Slanga BJ,Sulpizio AC,Hieble JP,Wawro JE,Kruse LI

    更新日期：1986-11-01 00:00:00

  • Development of N-methyl-(2-arylquinolin-4-yl)oxypropanamides as leads to PET radioligands for translocator protein (18 kDa).

    abstract：:Translocator protein (18 kDa), known as TSPO, is a recognized biomarker of neuroinflammation. Radioligands with PET accurately quantify TSPO in neuroinflammatory conditions. However, the existence of three human TSPO genotypes that show differential affinity to almost all useful TSPO PET radioligands hampers such stud...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm5007947

    authors： Brouwer C,Jenko K,Zoghbi SS,Innis RB,Pike VW

    更新日期：2014-07-24 00:00:00

  • Design and optimization of a series of 1-sulfonylpyrazolo[4,3-b]pyridines as selective c-Met inhibitors.

    abstract：:c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm502018y

    authors： Ma Y,Sun G,Chen D,Peng X,Chen YL,Su Y,Ji Y,Liang J,Wang X,Chen L,Ding J,Xiong B,Ai J,Geng M,Shen J

    更新日期：2015-03-12 00:00:00

  • Generation of ligand conformations in continuum solvent consistent with protein active site topology: application to thrombin.

    abstract：:Using the crystal structure of an inhibitor complexed with the serine protease thrombin (PDB code ) and the functional group definitions contained within the Catalyst software, a representation of the enzyme's active site was produced (structure-based pharmacophore model). A training set of 16 homologous non-peptide i...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm021028j

    authors： Greenidge PA,Mérette SA,Beck R,Dodson G,Goodwin CA,Scully MF,Spencer J,Weiser J,Deadman JJ

    更新日期：2003-04-10 00:00:00

  • Improved scoring of ligand-protein interactions using OWFEG free energy grids.

    abstract：:A new approach to rapidly score protein-ligand interactions is tested on several protein-ligand systems. Results using this approach - the OWFEG free energy grid - are quite promising and are generally in better agreement with experiment (in some cases much better) than those obtained employing scoring techniques curr...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm000375v

    authors： Pearlman DA,Charifson PS

    更新日期：2001-02-15 00:00:00

  • Synthesis and biological evaluation of a new series of hexahydro-2H-pyrano[3,2-c]quinolines as novel selective σ1 receptor ligands.

    abstract：:The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm400181k

    authors： Díaz JL,Christmann U,Fernández A,Luengo M,Bordas M,Enrech R,Carro M,Pascual R,Burgueño J,Merlos M,Benet-Buchholz J,Cerón-Bertran J,Ramírez J,Reinoso RF,Fernández de Henestrosa AR,Vela JM,Almansa C

    更新日期：2013-05-09 00:00:00

  • Mining Natural Products for Macrocycles to Drug Difficult Targets.

    abstract：:Lead generation for difficult-to-drug targets that have large, featureless, and highly lipophilic or highly polar and/or flexible binding sites is highly challenging. Here, we describe how cores of macrocyclic natural products can serve as a high-quality in silico screening library that provides leads for difficult-to...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.0c01569

    authors： Begnini F,Poongavanam V,Over B,Castaldo M,Geschwindner S,Johansson P,Tyagi M,Tyrchan C,Wissler L,Sjö P,Schiesser S,Kihlberg J

    更新日期：2021-01-28 00:00:00

  • Jatrophane diterpenes as modulators of multidrug resistance. Advances of structure-activity relationships and discovery of the potent lead pepluanin A.

    abstract：:From the whole plant of Euphorbia peplus L., five new diterpenes based on a jatrophane skeleton (pepluanins A-E, 1-5) were isolated, together with two known analogues (6 and 7), which served to divulge in detail the structure-activity relationships within this class of P-glycoprotein inhibitors. The results revealed t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm030951y

    authors： Corea G,Fattorusso E,Lanzotti V,Motti R,Simon PN,Dumontet C,Di Pietro A

    更新日期：2004-02-12 00:00:00

  • A Rhodium(III) Complex as an Inhibitor of Neural Precursor Cell Expressed, Developmentally Down-Regulated 8-Activating Enzyme with in Vivo Activity against Inflammatory Bowel Disease.

    abstract：:We report herein the identification of the rhodium(III) complex [Rh(phq)2(MOPIP)]+ (1) as a potent and selective ATP-competitive neural precursor cell expressed, developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) inhibitor. Structure-activity relationship analysis indicated that the overall organometalli...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00250

    authors： Zhong HJ,Wang W,Kang TS,Yan H,Yang Y,Xu L,Wang Y,Ma DL,Leung CH

    更新日期：2017-01-12 00:00:00

  • Quinazoline antifolates inhibiting thymidylate synthase: 2-desamino derivatives with enhanced solubility and potency.

    abstract：:The poor solubility of the thymidylate synthase (TS) inhibiting antifolate 10-propargyl-5,8-dideazafolic acid has posed problems for its clinical use and is probably responsible for its renal toxicity. The insolubility is caused by the 2-amino-3,4-dihydro-4-oxopyrimidine moiety of the drug which stabilizes the solid s...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00124a018

    authors： Jones TR,Thornton TJ,Flinn A,Jackman AL,Newell DR,Calvert AH

    更新日期：1989-04-01 00:00:00

  • Selection of evodiamine as a novel topoisomerase I inhibitor by structure-based virtual screening and hit optimization of evodiamine derivatives as antitumor agents.

    abstract：:Human topoisomerase I (TopoI) is recognized as a valuable target for the development of effective antitumor agents. Structure-based virtual screening was applied to the discovery of structurally diverse TopoI inhibitors. From 23 compounds selected by virtual screening, a total of 14 compounds were found to be TopoI in...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm100387d

    authors： Dong G,Sheng C,Wang S,Miao Z,Yao J,Zhang W

    更新日期：2010-11-11 00:00:00

  • N-cycloalkyl derivatives of adenosine and 1-deazaadenosine as agonists and partial agonists of the A(1) adenosine receptor.

    abstract：:A number of cycloalkyl substituents (from C-3 to C-8) have been introduced on the 6-amino group of adenosine, 1-deazaadenosine, and 2'-deoxyadenosine, bearing or not a chlorine atom at the 2-position, to evaluate the influence on the A(1) and A(2A) affinity of steric hindrance and lipophilicity. Furthermore, the guano...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9911231

    authors： Vittori S,Lorenzen A,Stannek C,Costanzi S,Volpini R,IJzerman AP,Kunzel JK,Cristalli G

    更新日期：2000-01-27 00:00:00

  • Synthesis, structure-activity relationships, and antitumor studies of 2-benzoxazolyl hydrazones derived from alpha-(N)-acyl heteroaromatics.

    abstract：:Recently we have described the antitumor activities of 2-benzoxazolylhydrazones derived from 2-formyl and 2-acetylpyridines. In search of a more efficacious analogue, compounds in which the 2-acetylpyridine moiety has been replaced by 2-acylpyridine and alpha-(N)-acetyldiazine/quinoline groups have been synthesized. T...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm060232u

    authors： Easmon J,Pürstinger G,Thies KS,Heinisch G,Hofmann J

    更新日期：2006-10-19 00:00:00

  • An X-ray crystallographic study of the nonsteroidal contraceptive agent centchroman.

    abstract：:We have determined an X-ray crystal structure for the N-methyl iodide derivative of the nonsteroidal contraceptive centchroman. The pendant aromatic substituents on C-3 and C-4 of the chroman system are nearly perpendicular to the plane of the chroman system, an orientation expected in such a chroman, but perturbed to...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00031a020

    authors： Ray S,Tandon A,Dwivedy I,Wilson SR,O'Neil JP,Katzenellenbogen JA

    更新日期：1994-03-04 00:00:00

  • Synthesis and in vitro multidrug resistance modulating activity of a series of dihydrobenzopyrans and tetrahydroquinolines.

    abstract：:A series of dihydrobenzopyrans and tetrahydroquinolines was synthesized and pharmacologically tested for their ability to inhibit P-glycoprotein mediated daunomycin efflux in multidrug resistant CCRF-CEM vcr1000 cells. Several compounds exhibit activities in the range of the reference compounds verapamil and propafeno...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm980517+

    authors： Hiessböck R,Wolf C,Richter E,Hitzler M,Chiba P,Kratzel M,Ecker G

    更新日期：1999-06-03 00:00:00

  • CNS drug design: balancing physicochemical properties for optimal brain exposure.

    abstract：:The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing molecules that can overcome this protection system and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major chal...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1021/jm501535r

    authors： Rankovic Z

    更新日期：2015-03-26 00:00:00

  • Synthesis and biological activity of a ketomethylene analogue of a tripeptide inhibitor of angiotensin converting enzyme.

    abstract：:An analogue of a tripeptide inhibitor of angiotensin converting enzyme, Bz-Phe-Gly-Pro, has been synthesized in which the amide bond connecting phenylalanine and glycine has been replaced by a ketomethylene group. This nonpeptide analogue, 20, shows more potent converting enzyme inhibiting activity, I50 = 0.07 microM,...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00186a020

    authors： Almquist RG,Chao WR,Ellis ME,Johnson HL

    更新日期：1980-12-01 00:00:00

  • Basic quinolinonyl diketo acid derivatives as inhibitors of HIV integrase and their activity against RNase H function of reverse transcriptase.

    abstract：:A series of antiviral basic quinolinonyl diketo acid derivatives were developed as inhibitors of HIV-1 IN. Compounds 12d,f,i inhibited HIV-1 IN with IC50 values below 100 nM for strand transfer and showed a 2 order of magnitude selectivity over 3'-processing. These strand transfer selective inhibitors also inhibited H...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm5001503

    authors： Costi R,Métifiot M,Chung S,Cuzzucoli Crucitti G,Maddali K,Pescatori L,Messore A,Madia VN,Pupo G,Scipione L,Tortorella S,Di Leva FS,Cosconati S,Marinelli L,Novellino E,Le Grice SF,Corona A,Pommier Y,Marchand C,Di San

    更新日期：2014-04-24 00:00:00

  • Efficient preparations of the beta-glucuronides of dihydroartemisinin and structural confirmation of the human glucuronide metabolite.

    abstract：:New and greatly improved preparations of the 12alpha,1'beta- (5) and 12beta,1'beta- (6) glucuronides of dihydroartemisinin (DHA, 2) are reported using anomeric hydroxy and imidate glucuronate intermediates. Comparison of the synthetic and natural materials shows that the human metabolite of DHA is the 12alpha-epimer 5...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm001061a

    authors： O'Neill PM,Scheinmann F,Stachulski AV,Maggs JL,Park BK

    更新日期：2001-04-26 00:00:00

  • Methyl analogues of the experimental Alzheimer drug phenserine: synthesis and structure/activity relationships for acetyl- and butyrylcholinesterase inhibitory action.

    abstract：:With the goal of developing potential Alzheimer's pharmacotherapeutics, we have synthesized a series of novel analogues of the potent anticholinesterases phenserine (2) and physostigmine (1). These derivatives contain methyl (3, 4, 6), dimethyl (5, 7, 8, 10, 11) and trimethyl (14) substituents in each position of the ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm010080x

    authors： Yu Q,Holloway HW,Flippen-Anderson JL,Hoffman B,Brossi A,Greig NH

    更新日期：2001-11-22 00:00:00

  • Discovery and Optimization of a Porcupine Inhibitor.

    abstract：:Wnt proteins regulate various cellular functions and serve distinct roles in normal development throughout life. Wnt signaling is dysregulated in various diseases including cancers. Porcupine (PORCN) is a membrane-bound O-acyltransferase that palmitoleates the Wnts and hence is essential for their secretion and functi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.5b00507

    authors： Duraiswamy AJ,Lee MA,Madan B,Ang SH,Tan ES,Cheong WW,Ke Z,Pendharkar V,Ding LJ,Chew YS,Manoharan V,Sangthongpitag K,Alam J,Poulsen A,Ho SY,Virshup DM,Keller TH

    更新日期：2015-08-13 00:00:00

  • Synthesis and antimalarial activity of 2-guanidino-4-oxoimidazoline derivatives.

    abstract：:A series of 2-guanidino-4-oxoimidazoline (deoxo-IZ) derivatives was prepared and showed potent antimalarial activities in rodent and Rhesus models. Compound 8e, the most potent analogues of this series, is the first non-8-aminoqinoline antimalarial that demonstrated radical curative activity in non-human primate by or...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm200111g

    authors： Liu X,Wang X,Li Q,Kozar MP,Melendez V,O'Neil MT,Lin AJ

    更新日期：2011-07-14 00:00:00

  • Synthesis and in vivo antitumor activity of 2-amino-9H-purine-6-sulfenamide, -sulfinamide, and -sulfonamide and related purine ribonucleosides.

    abstract：:A number of 6-sulfenamide, 6-sulfinamide, and 6-sulfonamide derivatives of 2-aminopurine and certain related purine ribonucleosides have been synthesized and evaluated for antileukemic activity in mice. Amination of 6-mercaptopurine ribonucleoside (7a) and 6-thioguanosine (7b) with chloramine solution gave 9-beta-D-ri...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00163a020

    authors： Revankar GR,Hanna NB,Imamura N,Lewis AF,Larson SB,Finch RA,Avery TL,Robins RK

    更新日期：1990-01-01 00:00:00

  • Discovery of a series of imidazo[4,5-b]pyridines with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ.

    abstract：:Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of th...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm200409s

    authors： Casimiro-Garcia A,Filzen GF,Flynn D,Bigge CF,Chen J,Davis JA,Dudley DA,Edmunds JJ,Esmaeil N,Geyer A,Heemstra RJ,Jalaie M,Ohren JF,Ostroski R,Ellis T,Schaum RP,Stoner C

    更新日期：2011-06-23 00:00:00

  • Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate.

    abstract：:A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this comp...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm980077m

    authors： Wong WC,Chiu G,Wetzel JM,Marzabadi MR,Nagarathnam D,Wang D,Fang J,Miao SW,Hong X,Forray C,Vaysse PJ,Branchek TA,Gluchowski C,Tang R,Lepor H

    更新日期：1998-07-02 00:00:00

  • Synthesis and structure-activity relationships of new 9-N-alkyl derivatives of 9(S)-erythromycylamine.

    abstract：:A series of new 9-N-alkyl derivatives of 9(S)-erythromycylamine has been synthesized by reductive alkylation of erythromycylamine with aliphatic aldehydes and sodium cyanoborohydride. Alternative syntheses employing hydrogenation methods have also been developed. These new 9-N-alkyl derivatives possess excellent antim...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00173a028

    authors： Kirst HA,Wind JA,Leeds JP,Willard KE,Debono M,Bonjouklian R,Greene JM,Sullivan KA,Paschal JW,Deeter JB

    更新日期：1990-11-01 00:00:00

  • 1,4-Dihydropyridines as antagonists of platelet activating factor. 1. Synthesis and structure-activity relationships of 2-(4-heterocyclyl)phenyl derivatives.

    abstract：:A novel class of 2-(4-heterocyclylphenyl)-1,4-dihydropyridines (2-38) possessing antagonist activity against platelet activating factor (PAF) was prepared by the Hantzsch synthesis from a variety of ethyl 4'-heterocyclic-substituted benzoylacetates, aryl or heteroaryl aldehydes, and substituted 3-aminocrotonamides or ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00095a005

    authors： Cooper K,Fray MJ,Parry MJ,Richardson K,Steele J

    更新日期：1992-08-21 00:00:00

  • Analysis of the binding of mixed lineage leukemia 1 (MLL1) and histone 3 peptides to WD repeat domain 5 (WDR5) for the design of inhibitors of the MLL1-WDR5 interaction.

    abstract：:MLL1 is a histone 3 lysine 4 (H3K4) methyltransferase and a promising new cancer therapeutic target. The catalytic activity of MLL1 is regulated by the formation of a core complex consisting of MLL1, WDR5, RbBP5, and Ash2L. The interaction between WDR5 and MLL1 plays an essential role in regulation of the H3K4 methylt...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm100139b

    authors： Karatas H,Townsend EC,Bernard D,Dou Y,Wang S

    更新日期：2010-07-22 00:00:00