abstract：:Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resist...

journal_title：Journal of medicinal chemistry

authors： Skepper CK,Armstrong D,Balibar CJ,Bauer D,Bellamacina C,Benton BM,Bussiere D,De Pascale G,De Vicente J,Dean CR,Dhumale B,Fisher LM,Fuller J,Fulsunder M,Holder LM,Hu C,Kantariya B,Lapointe G,Leeds JA,Li X,Lu P,Lv

更新日期：2020-07-23 00:00:00

abstract：:A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A2BAR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, which contain 18 differe...

journal_title：Journal of medicinal chemistry

authors： Mallo-Abreu A,Prieto-Díaz R,Jespers W,Azuaje J,Majellaro M,Velando C,García-Mera X,Caamaño O,Brea J,Loza MI,Gutiérrez-de-Terán H,Sotelo E

更新日期：2020-07-23 00:00:00

abstract：:In this work, a series of water-soluble propofol prodrugs were synthesized, and their propofol release rate and pharmacodynamic characteristics were measured. We found that inserting glycolic acid as a linker between propofol and the cyclic amino acid accelerated the release of propofol from prodrugs into the plasma w...

journal_title：Journal of medicinal chemistry

authors： Liu LQ,Hong PX,Song XH,Zhou CC,Ling R,Kang Y,Qi QR,Yang J

更新日期：2020-07-23 00:00:00

abstract：:Owing to the emergence of drug resistance and high morbidity and mortality, the need for novel anti-influenza A virus (IAV) drugs with divergent targets is highly sought after. Herein, we reveal the discovery of an anti-IAV agent as a dual inhibitor to block hemagglutinin-mediated adsorption and membrane fusion using ...

journal_title：Journal of medicinal chemistry

authors： Wu G,Yu G,Yu Y,Yang S,Duan Z,Wang W,Liu Y,Yu R,Li J,Zhu T,Gu Q,Li D

更新日期：2020-07-09 00:00:00

abstract：:Continuing our search for vitamin D analogues, we explored the modification of the steroidal side chain and inserted a methylene moiety in position C-22 together with either lengthening the side chain or introducing a ring at the terminal end. Our conformational studies confirmed that the presence of a methylene group...

journal_title：Journal of medicinal chemistry

authors： Sibilska-Kaminski IK,Sicinski RR,Plum LA,DeLuca HF

更新日期：2020-07-09 00:00:00

abstract：:Identifying local similarities in binding sites from distant proteins is a major hurdle to rational drug design. We herewith present a novel method, borrowed from computer vision, adapted to mine fragment subpockets and compare them to whole ligand-binding sites. Pockets are represented by pharmacophore-annotated poin...

journal_title：Journal of medicinal chemistry

authors： Eguida M,Rognan D

更新日期：2020-07-09 00:00:00

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

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

abstract：:Inhibition of embryonic ectoderm development (EED) is a new cancer therapeutic strategy. Herein, we report our discovery of EEDi-5285 as an exceptionally potent, efficacious, and orally active EED inhibitor. EEDi-5285 binds to the EED protein with an IC50 value of 0.2 nM and inhibits cell growth with IC50 values of 20...

journal_title：Journal of medicinal chemistry

authors： Rej RK,Wang C,Lu J,Wang M,Petrunak E,Zawacki KP,McEachern D,Fernandez-Salas E,Yang CY,Wang L,Li R,Chinnaswamy K,Wen B,Sun D,Stuckey J,Zhou Y,Chen J,Tang G,Wang S

更新日期：2020-07-09 00:00:00

abstract：:Stabilization of protein-protein interactions (PPIs) holds great potential for therapeutic agents, as illustrated by the successful drugs rapamycin and lenalidomide. However, how such interface-binding molecules can be created in a rational, bottom-up manner is a largely unanswered question. We report here how a fragm...

journal_title：Journal of medicinal chemistry

authors： Guillory X,Wolter M,Leysen S,Neves JF,Kuusk A,Genet S,Somsen B,Morrow JK,Rivers E,van Beek L,Patel J,Goodnow R,Schoenherr H,Fuller N,Cao Q,Doveston RG,Brunsveld L,Arkin MR,Castaldi P,Boyd H,Landrieu I,Chen H,O

更新日期：2020-07-09 00:00:00

abstract：:This is a review of the macrolide and ketolide field focusing on differentiating the pharmacodynamics and especially the toxicology of the macrolides and ketolides. We emphasize the diversity in pharmacodynamics and toxicity of the macrolides and ketolides, resulting from even small structural changes, which makes it ...

journal_title：Journal of medicinal chemistry

authors： Fernandes P,Pereira D,Watkins PB,Bertrand D

更新日期：2020-06-25 00:00:00

abstract：:The efficacious dose of a drug is perhaps the most holistic metric reflecting its therapeutic potential. Dose is predicted at many stages in drug discovery and development. Prior to the 1990s, dose prediction was limited to the drug "working" at a reasonable dose and dose regimen in an animal model. Through the early ...

journal_title：Journal of medicinal chemistry

authors： Maurer TS,Smith D,Beaumont K,Di L

更新日期：2020-06-25 00:00:00

abstract：:Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) characterized by liver steatosis, inflammation, and hepatocellular damage. NASH is a serious condition that can progress to cirrhosis, liver failure, and hepatocellular carcinoma. The association of NASH with obesity, type...

journal_title：Journal of medicinal chemistry

authors： Romero FA,Jones CT,Xu Y,Fenaux M,Halcomb RL

更新日期：2020-05-28 00:00:00

abstract：:USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemica...

journal_title：Journal of medicinal chemistry

authors： Leger PR,Hu DX,Biannic B,Bui M,Han X,Karbarz E,Maung J,Okano A,Osipov M,Shibuya GM,Young K,Higgs C,Abraham B,Bradford D,Cho C,Colas C,Jacobson S,Ohol YM,Pookot D,Rana P,Sanchez J,Shah N,Sun M,Wong S,Brocks

更新日期：2020-05-28 00:00:00

abstract：:Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to no...

journal_title：Journal of medicinal chemistry

authors： Lucas SCC,Atkinson SJ,Bamborough P,Barnett H,Chung CW,Gordon L,Mitchell DJ,Phillipou A,Prinjha RK,Sheppard RJ,Tomkinson NCO,Watson RJ,Demont EH

更新日期：2020-05-28 00:00:00

abstract：:We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this a...

journal_title：Journal of medicinal chemistry

authors： Nishimura Y,Esaki T,Isshiki Y,Furuta Y,Mizutani A,Kotake T,Emura T,Watanabe Y,Ohta M,Nakagawa T,Ogawa K,Arai S,Noda H,Kitamura H,Shimizu M,Tamura T,Sato H

更新日期：2020-05-28 00:00:00

abstract：:Glioblastoma multiforme (GBM) is the deadliest form of brain tumor. It is known for its ability to escape the therapeutic options available to date thanks to the presence of a subset of cells endowed with stem-like properties and ability to resist to cytotoxic treatments. As the cytosolic enzyme aldehyde dehydrogenase...

journal_title：Journal of medicinal chemistry

authors： Quattrini L,Gelardi ELM,Coviello V,Sartini S,Ferraris DM,Mori M,Nakano I,Garavaglia S,La Motta C

更新日期：2020-05-14 00:00:00

abstract：:In humans, bitter taste is mediated by 25 TAS2Rs. Many compounds, including certain active pharmaceutical ingredients, excipients, and nutraceuticals, impart their bitter taste (or in part) through TAS2R8 activation. However, effective TAS2R8 blockers that can either suppress or reduce the bitterness of these compound...

journal_title：Journal of medicinal chemistry

authors： Fotsing JR,Darmohusodo V,Patron AP,Ching BW,Brady T,Arellano M,Chen Q,Davis TJ,Liu H,Servant G,Zhang L,Williams M,Saganich M,Ditschun T,Tachdjian C,Karanewsky DS

更新日期：2020-05-14 00:00:00

abstract：:Due to their role in many important signaling pathways, phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive targets for the development of experimental therapeutics for cancer, metabolic, and immunological disorders. Recent efforts to develop small molecule inhibitors for these lipid kinases resulted i...

journal_title：Journal of medicinal chemistry

authors： Manz TD,Sivakumaren SC,Ferguson FM,Zhang T,Yasgar A,Seo HS,Ficarro SB,Card JD,Shim H,Miduturu CV,Simeonov A,Shen M,Marto JA,Dhe-Paganon S,Hall MD,Cantley LC,Gray NS

更新日期：2020-05-14 00:00:00

abstract：:2-Phenylcyclopropylmethylamine (PCPMA) analogues have been reported as selective serotonin 2C agonists. On the basis of the same scaffold, we designed and synthesized a series of bitopic derivatives as dopamine D3R ligands. A number of these new compounds show a high binding affinity for D3R with excellent selectivity...

journal_title：Journal of medicinal chemistry

authors： Tan L,Zhou Q,Yan W,Sun J,Kozikowski AP,Zhao S,Huang XP,Cheng J

更新日期：2020-05-14 00:00:00

abstract：:The insertion of single 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres of trans-amide bonds (triazole scan) was recently applied to the 177Lu-labeled tumor-targeting analog of minigastrin, [Nle15]MG11. The reported novel mono-triazolo-peptidomimetics of [Nle15]MG11 showed either improved resist...

journal_title：Journal of medicinal chemistry

authors： Grob NM,Schmid S,Schibli R,Behe M,Mindt TL

更新日期：2020-05-14 00:00:00

abstract：:Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket ...

journal_title：Journal of medicinal chemistry

authors： Kettle JG,Bagal SK,Bickerton S,Bodnarchuk MS,Breed J,Carbajo RJ,Cassar DJ,Chakraborty A,Cosulich S,Cumming I,Davies M,Eatherton A,Evans L,Feron L,Fillery S,Gleave ES,Goldberg FW,Harlfinger S,Hanson L,Howard M,Howe

更新日期：2020-05-14 00:00:00

abstract：:The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold...

journal_title：Journal of medicinal chemistry

authors： Li Z,Xiao S,Yang Y,Chen C,Lu T,Chen Z,Jiang H,Chen S,Luo C,Zhou B

更新日期：2020-04-23 00:00:00

abstract：:A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC50 < 10 nM) and selective against PI3K...

journal_title：Journal of medicinal chemistry

authors： Thakur A,Tawa GJ,Henderson MJ,Danchik C,Liu S,Shah P,Wang AQ,Dunn G,Kabir M,Padilha EC,Xu X,Simeonov A,Kharbanda S,Stone R,Grewal G

更新日期：2020-04-23 00:00:00

abstract：:Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, an...

journal_title：Journal of medicinal chemistry

authors： Chianelli D,Rucker PV,Roland J,Tully DC,Nelson J,Liu X,Bursulaya B,Hernandez ED,Wu J,Prashad M,Schlama T,Liu Y,Chu A,Schmeits J,Huang DJ,Hill R,Bao D,Zoll J,Kim Y,Groessl T,McNamara P,Liu B,Richmond W,Sancho

更新日期：2020-04-23 00:00:00

abstract：:Tankyrases (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/β-catenin signaling, which plays an important role in cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent tankyrase i...

journal_title：Journal of medicinal chemistry

authors： Shirai F,Mizutani A,Yashiroda Y,Tsumura T,Kano Y,Muramatsu Y,Chikada T,Yuki H,Niwa H,Sato S,Washizuka K,Koda Y,Mazaki Y,Jang MK,Yoshida H,Nagamori A,Okue M,Watanabe T,Kitamura K,Shitara E,Honma T,Umehara T,Shi

更新日期：2020-04-23 00:00:00

abstract：:The immunoproteasome (iP), an inducible proteasome variant harboring three immunosubunits, low molecular mass polypeptide-2 (LMP2), multicatalytic endopeptidase complex subunit-1, and low molecular mass polypeptide-7 (LMP7), is involved in multiple facets of inflammatory responses. We recently reported that YU102, a d...

journal_title：Journal of medicinal chemistry

authors： Bhattarai D,Lee MJ,Baek A,Yeo IJ,Miller Z,Baek YM,Lee S,Kim DE,Hong JT,Kim KB

更新日期：2020-04-09 00:00:00

abstract：:Human African trypanosomiasis is causing thousands of deaths every year in the rural areas of Africa. In this manuscript we describe the optimization of a family of phtalazinone derivatives. Phosphodiesterases have emerged as attractive molecular targets for a novel treatment for a variety of neglected parasitic disea...

journal_title：Journal of medicinal chemistry

authors： Salado IG,Singh AK,Moreno-Cinos C,Sakaine G,Siderius M,Van der Veken P,Matheeussen A,van der Meer T,Sadek P,Gul S,Maes L,Sterk GJ,Leurs R,Brown D,Augustyns K

更新日期：2020-04-09 00:00:00

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

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

abstract：:Increased usage of daptomycin to treat infections caused by Gram-positive bacterial pathogens has resulted in emergence of resistant mutants. In a search for more effective daptomycin analogues through medicinal chemistry studies, we found that methylation at the nonproteinogenic amino acid kynurenine in daptomycin co...

journal_title：Journal of medicinal chemistry

authors： Chow HY,Po KHL,Gao P,Blasco P,Wang X,Li C,Ye L,Jin K,Chen K,Chan EWC,You X,Yi Tsun Kao R,Chen S,Li X

更新日期：2020-03-26 00:00:00

abstract：:Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are α-(l)-amino acids. In this study, we aimed to determine ...

journal_title：Journal of medicinal chemistry

authors： Kim K,Kwon H,Barinka C,Motlova L,Nam S,Choi D,Ha H,Nam H,Son SH,Minn I,Pomper MG,Yang X,Kutil Z,Byun Y

更新日期：2020-03-26 00:00:00

abstract：:Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhib...

journal_title：Journal of medicinal chemistry

authors： Xie Y,Tummala P,Oakley AJ,Deora GS,Nakano Y,Rooke M,Cuellar ME,Strasser JM,Dahlin JL,Walters MA,Casarotto MG,Board PG,Baell JB

更新日期：2020-03-26 00:00:00

abstract：:Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A ...

journal_title：Journal of medicinal chemistry

authors： Liu YA,Jin Q,Zou Y,Ding Q,Yan S,Wang Z,Hao X,Nguyen B,Zhang X,Pan J,Mo T,Jacobsen K,Lam T,Wu TY,Petrassi HM,Bursulaya B,DiDonato M,Gordon WP,Liu B,Baaten J,Hill R,Nguyen-Tran V,Qiu M,Zhang YQ,Kamireddy A,

更新日期：2020-03-26 00:00:00

abstract：:Recently, our group identified that harmine is able to induce β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure-activity relationships for harmi...

journal_title：Journal of medicinal chemistry

authors： Kumar K,Wang P,Wilson J,Zlatanic V,Berrouet C,Khamrui S,Secor C,Swartz EA,Lazarus M,Sanchez R,Stewart AF,Garcia-Ocana A,DeVita RJ

更新日期：2020-03-26 00:00:00

abstract：:Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention toward that go...

journal_title：Journal of medicinal chemistry

authors： Rueda-Zubiaurre A,Yahiya S,Fischer OJ,Hu X,Saunders CN,Sharma S,Straschil U,Shen J,Tate EW,Delves MJ,Baum J,Barnard A,Fuchter MJ

更新日期：2020-03-12 00:00:00

abstract：:A novel series of C(3)-substituted piperdinylindoles were developed as nociceptin opioid receptor (NOP) partial agonists to explore a pharmacological hypothesis that NOP partial agonists would afford a dual pharmacological action of attenuating Parkinson's disease (PD) motor symptoms and development of levodopa-induce...

journal_title：Journal of medicinal chemistry

authors： Kamakolanu UG,Meyer ME,Yasuda D,Polgar WE,Marti M,Mercatelli D,Pisanò CA,Brugnoli A,Morari M,Zaveri NT

更新日期：2020-03-12 00:00:00

abstract：:The AAA+ ATPase, p97, also referred to as VCP, plays an essential role in cellular homeostasis by regulating endoplasmic reticulum-associated degradation (ERAD), mitochondrial-associated degradation (MAD), chromatin-associated degradation, autophagy, and endosomal trafficking. Mutations in p97 have been linked to a nu...

journal_title：Journal of medicinal chemistry

authors： Huryn DM,Kornfilt DJP,Wipf P

更新日期：2020-03-12 00:00:00

abstract：:The therapeutic success of peptidic GLP-1 receptor agonists for treatment of type 2 diabetes mellitus (T2DM) motivated our search for orally bioavailable small molecules that can activate the GLP-1 receptor (GLP-1R) as a well-validated target for T2DM. Here, the discovery and characterization of a potent and selective...

journal_title：Journal of medicinal chemistry

authors： Méndez M,Matter H,Defossa E,Kurz M,Lebreton S,Li Z,Lohmann M,Löhn M,Mors H,Podeschwa M,Rackelmann N,Riedel J,Safar P,Thorpe DS,Schäfer M,Weitz D,Breitschopf K

更新日期：2020-03-12 00:00:00

abstract：:The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-...

journal_title：Journal of medicinal chemistry

authors： Li G,Meanwell NA,Krystal MR,Langley DR,Naidu BN,Sivaprakasam P,Lewis H,Kish K,Khan JA,Ng A,Trainor GL,Cianci C,Dicker IB,Walker MA,Lin Z,Protack T,Discotto L,Jenkins S,Gerritz SW,Pendri A

更新日期：2020-03-12 00:00:00

abstract：:5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisome...

journal_title：Journal of medicinal chemistry

authors： Chatzopoulou M,Claridge TDW,Davies KE,Davies SG,Elsey DJ,Emer E,Fletcher AM,Harriman S,Robinson N,Rowley JA,Russell AJ,Tinsley JM,Weaver R,Wilkinson IVL,Willis NJ,Wilson FX,Wynne GM

更新日期：2020-03-12 00:00:00

abstract：:Hyperfibrinolytic situations can lead to life-threatening bleeding, especially during cardiac surgery. The approved antifibrinolytic agents such as tranexamic acid, ε-aminocaproic acid, 4-aminomethylbenzoic acid, and aprotinin were developed in the 1960s without the structural insight of their respective targets. Crys...

journal_title：Journal of medicinal chemistry

authors： Steinmetzer T,Pilgram O,Wenzel BM,Wiedemeyer SJA

更新日期：2020-02-27 00:00:00