G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment of Diabetes: Recent Progress and Prevailing Challenges.


:In this Perspective, recent advances and challenges in the development of GPR119 agonists as new oral antidiabetic drugs will be discussed. Such agonists are expected to exhibit a low risk to induce hypoglycemia as well as to have a beneficial impact on body weight. Many pharmaceutical companies have been active in the search for GPR119 agonists, making it a highly competitive area in the industrial environment. Several GPR119 agonists have been entered into clinical studies, but many have failed either in phase I or II and none has progressed beyond phase II. Herein we describe the strategies chosen by the different medicinal chemistry teams in academia and the pharmaceutical industry to improve potency, physicochemical properties, pharmacokinetics, and the safety profile of GPR119 agonists in the discovery phase in order to improve the odds for successful development.


J Med Chem


Ritter K,Buning C,Halland N,Pöverlein C,Schwink L




Has Abstract


2016-04-28 00:00:00












  • Enzymatic release of antitumor ether lipids by specific phospholipase A2 activation of liposome-forming prodrugs.

    abstract::An enzymatically activated liposome-based drug-delivery concept involving masked antitumor ether lipids (AELs) has been investigated. This concept takes advantage of the cytotoxic properties of AEL drugs as well as the membrane permeability enhancing properties of these molecules, which can lead to enhanced drug diffu...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Andresen TL,Davidsen J,Begtrup M,Mouritsen OG,Jørgensen K

    更新日期:2004-03-25 00:00:00

  • Development and validation of k-nearest-neighbor QSPR models of metabolic stability of drug candidates.

    abstract::Computational ADME (absorption, distribution, metabolism, and excretion) models may be used early in the drug discovery process in order to flag drug candidates with potentially problematic ADME profiles. We report the development, validation, and application of quantitative structure-property relationship (QSPR) mode...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Shen M,Xiao Y,Golbraikh A,Gombar VK,Tropsha A

    更新日期:2003-07-03 00:00:00

  • Carbonic anhydrase inhibitors: synthesis of water-soluble, aminoacyl/dipeptidyl sulfonamides possessing long-lasting intraocular pressure-lowering properties via the topical route.

    abstract::Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino, or hydroxyl groups with Boc-Gly, Boc-Sar, TrS-Crt, or Boc-Gly-Gly (Sar = sarcosine, N-Me-Gly; Crt = creatine, N-amidinosarcosine; TrS = tritylsulfenyl; Boc = tert-butoxycarbonyl) in the presence of carbodiimide derivatives afforded a...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


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    abstract::The importance of steric factors in quantitative structure-activity relationships involving steroid hormones is discussed. a variety of steric parameters, such as parachlor, molecular volume, van der Waals volume, and including difference and squared steric terms, is explored in an attempt to find preferred forms for...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Coburn RA,Solo AJ

    更新日期:1976-06-01 00:00:00

  • Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders.

    abstract::Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium; agonism of PPARα with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal disea...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Dou X,Nath D,Shin H,Nurmemmedov E,Bourne PC,Ma JX,Duerfeldt AS

    更新日期:2020-03-26 00:00:00

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    abstract::Our exploratory study was based on the concept that a non-amidine factor Xa (fXa) inhibitor is suitable for an orally available anticoagulant. We synthesized and evaluated a series of N-(6-chloronaphthalen-2-yl)sulfonylpiperazine derivatives incorporating various fused-bicyclic rings containing an aliphatic amine expe...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


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    journal_title:Journal of medicinal chemistry

    pub_type: 信件


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    更新日期:2002-03-28 00:00:00

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    pub_type: 杂志文章


    authors: Bautista-Aguilera ÓM,Budni J,Mina F,Medeiros EB,Deuther-Conrad W,Entrena JM,Moraleda I,Iriepa I,López-Muñoz F,Marco-Contelles J

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    pub_type: 杂志文章


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    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


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    更新日期:1994-11-25 00:00:00

  • Antimicrobial and cytotoxic properties of 9,10-dihydrophenanthrenes: structure-activity studies on juncusol.

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    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


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    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


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    更新日期:2006-07-13 00:00:00

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    abstract::Drugs exert desired and undesired effects based on their binding interactions with protein target(s) and off-target(s), providing evidence for drug efficacy and toxicity. Pioglitazone and rosiglitazone possess a common functional core, glitazone, which is considered a privileged scaffold upon which to build a drug sel...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Hoffmann BR,El-Mansy MF,Sem DS,Greene AS

    更新日期:2012-10-11 00:00:00

  • How Frequently Are Pan-Assay Interference Compounds Active? Large-Scale Analysis of Screening Data Reveals Diverse Activity Profiles, Low Global Hit Frequency, and Many Consistently Inactive Compounds.

    abstract::Undetected pan-assay interference compounds (PAINS) with false-positive activities in assays often propagate through medicinal chemistry programs and compromise their outcomes. Although a large number of PAINS have been classified, often on the basis of individual studies or chemical experience, little has been done s...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Jasial S,Hu Y,Bajorath J

    更新日期:2017-05-11 00:00:00

  • Adenosine mimetics as inhibitors of NAD+-dependent histone deacetylases, from kinase to sirtuin inhibition.

    abstract::NAD+-dependent histone deacetylases, sirtuins, cleave acetyl groups from lysines of histones and other proteins to regulate their activity. Identification of potent selective inhibitors would help to elucidate sirtuin biology and could lead to useful therapeutic agents. NAD+ has an adenosine moiety that is also presen...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Trapp J,Jochum A,Meier R,Saunders L,Marshall B,Kunick C,Verdin E,Goekjian P,Sippl W,Jung M

    更新日期:2006-12-14 00:00:00

  • Oxadiazoles in medicinal chemistry.

    abstract::Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Boström J,Hogner A,Llinàs A,Wellner E,Plowright AT

    更新日期:2012-03-08 00:00:00

  • 8-Substituted analogues of 3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine: highly potent and selective PDE4 inhibitors.

    abstract::3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine V11294 (1) has been identified as a lead structure, which selectively inhibits human lung PDE4 (436 nM) and is also active in a number of in vitro and in vivo models of inflammation. Here we describe the synthesis and pharmacology of a series of highly potent 8...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Whitehead JW,Lee GP,Gharagozloo P,Hofer P,Gehrig A,Wintergerst P,Smyth D,McCoull W,Hachicha M,Patel A,Kyle DJ

    更新日期:2005-02-24 00:00:00

  • 4-[omega-[4-arylpiperazin-1-yl]alkoxy]phenyl)imidazo[1,2-a]pyridine derivatives: fluorescent high-affinity dopamine D3 receptor ligands as potential probes for receptor visualization.

    abstract::Sixteen long-chain arylpiperazines bearing the fluorescent moiety 2-phenylimidazo[1,2-a]pyridine were synthesized as fluorescent dopamine D3 receptors ligands (385 nM < Ki < 0.72 nM). The most potent D3 compounds 15a and 19a (Ki = 1.6 and 0.72 nM, respectively) showed good Stokes shift and high quantum yield in ethano...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Leopoldo M,Lacivita E,Passafiume E,Contino M,Colabufo NA,Berardi F,Perrone R

    更新日期:2007-10-04 00:00:00

  • Thiazolopyridine ureas as novel antitubercular agents acting through inhibition of DNA Gyrase B.

    abstract::A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration o...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Kale MG,Raichurkar A,P SH,Waterson D,McKinney D,Manjunatha MR,Kranthi U,Koushik K,Jena Lk,Shinde V,Rudrapatna S,Barde S,Humnabadkar V,Madhavapeddi P,Basavarajappa H,Ghosh A,Ramya VK,Guptha S,Sharma S,Vachaspati P,

    更新日期:2013-11-14 00:00:00

  • Discovery and investigation of antiproliferative and apoptosis-inducing properties of new heterocyclic podophyllotoxin analogues accessible by a one-step multicomponent synthesis.

    abstract::Podophyllotoxin has been extensively used as a lead agent in the development of new anticancer drugs. On the basis of the previously reported simplified 4-aza-2,3-didehydro podophyllotoxin analogues, we implemented a bioisosteric replacement of the methylenedioxybenzene subunit with a pyrazole moiety to afford tetracy...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Magedov IV,Manpadi M,Slambrouck SV,Steelant WF,Rozhkova E,Przheval'skii NM,Rogelj S,Kornienko A

    更新日期:2007-10-18 00:00:00

  • Selective protection and functionalization of morphine: synthesis and opioid receptor binding properties of 3-amino-3-desoxymorphine derivatives.

    abstract::As part of an effort to identify novel opioid receptor interactive agents, we recently prepared a series of 8-(substituted)amino analogues of cyclazocine. We found the chiral 8-phenylamino (NHC(6)H(5)) cyclazocine derivative to have subnanomolar affinity for kappa opioid receptors and a 2-fold lower affinity for mu, o...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Wentland MP,Duan W,Cohen DJ,Bidlack JM

    更新日期:2000-09-21 00:00:00

  • Discovery of Novel Multifunctional Ligands with μ/δ Opioid Agonist/Neurokinin-1 (NK1) Antagonist Activities for the Treatment of Pain.

    abstract::Multifunctional ligands with agonist bioactivities at μ/δ opioid receptors (MOR/DOR) and antagonist bioactivity at the neurokinin-1 receptor (NK1R) have been designed and synthesized. These peptide-based ligands are anticipated to produce better biological profiles (e.g., higher analgesic effect with significantly les...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Giri AK,Apostol CR,Wang Y,Forte BL,Largent-Milnes TM,Davis P,Rankin D,Molnar G,Olson KM,Porreca F,Vanderah TW,Hruby VJ

    更新日期:2015-11-12 00:00:00

  • Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK).

    abstract::As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, in...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章,评审


    authors: Kong X,Pan P,Sun H,Xia H,Wang X,Li Y,Hou T

    更新日期:2019-12-26 00:00:00

  • ElogPoct: a tool for lipophilicity determination in drug discovery.

    abstract::We present an RP-HPLC method, for the determination of logPoct values for neutral drugs, which combines ease of operation with high accuracy and which has been shown to work for a set of 36 molecules comprised largely of drugs. The general features of the method are as follows: (i) compound sparing (< or = 1 mL of a 3...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Lombardo F,Shalaeva MY,Tupper KA,Gao F,Abraham MH

    更新日期:2000-07-27 00:00:00

  • Stereochemical requirements for cannabinoid activity.

    abstract::Several pairs of cannabinoid isomers were synthesized and tested for psychotropic activity in rhesus monkeys. Two regularities were observed: (a) In the absence of the other substituents, the equatorial stereochemistry of the substituent at C-1 determines activity. (b) Two groups of THC-type cannabinoids which differ ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


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    更新日期:1980-10-01 00:00:00

  • Microwave-assisted ring opening of epoxides: a general route to the synthesis of 1-aminopropan-2-ols with anti malaria parasite activities.

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    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Robin A,Brown F,Bahamontes-Rosa N,Wu B,Beitz E,Kun JF,Flitsch SL

    更新日期:2007-08-23 00:00:00

  • New antihistaminic N-heterocyclic 4-piperidinamines. 1. Synthesis and antihistaminic activity of N-(4-piperidinyl)-1H-benzimidazol-2-amines.

    abstract::The synthesis of a series N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vitro and in vivo antihistaminic activity are described. Cyclodesulfurization of (2-aminophenyl)thioureas with mercury(II) oxide resulted in 2-aminobenzimidazole intermediates, which were monoalkylated on th...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Janssens F,Torremans J,Janssen M,Stokbroekx RA,Luyckx M,Janssen PA

    更新日期:1985-12-01 00:00:00

  • Salicylanilide Analog Minimizes Relapse of Clostridioides difficile Infection in Mice.

    abstract::Clostridioides difficile infection (CDI) causes serious and sometimes fatal symptoms like diarrhea and pseudomembranous colitis. Although antibiotics for CDI exist, they are either expensive or cause recurrence of the infection due to their altering the colonic microbiota, which is necessary to suppress the infection....

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Blake S,Thanissery R,Rivera AJ,Hixon MS,Lin M,Theriot CM,Janda KD

    更新日期:2020-07-09 00:00:00

  • Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents.

    abstract::Acetylcholinesterase (AChE), a key enzyme in the central and peripheral nervous systems, is the principal target of organophosphorus nerve agents. Quaternary oximes can regenerate AChE activity by displacing the phosphyl group of the nerve agent from the active site, but they are poorly distributed in the central nerv...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Santoni G,de Sousa J,de la Mora E,Dias J,Jean L,Sussman JL,Silman I,Renard PY,Brown RCD,Weik M,Baati R,Nachon F

    更新日期:2018-09-13 00:00:00

  • 2,3-Disubstituted 1,8-naphthyridines as potential diuretic agents. 2. 5,7-Dimethyl derivatives.

    abstract::A variety of 2,3-disubstituted 5,7-dimethyl-1,8-naphthyridines was synthesized and tested in saline-loaded rats for their diuretic properties. The 2-amino-3-carbomethoxy and four 2-amino-3-N-alkylcarbamoyl compounds exhibited significant activity as measured by volume output; however, they were generally less potent t...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Hawes EM,Gorecki DK,Gedir RG

    更新日期:1977-06-01 00:00:00