abstract：:Singlet oxygen can severely damage biological tissue, which is exploited in photodynamic therapy (PDT). In PDT, the effective range is limited by the distribution of the photosensitizer (PS) and the illuminated area. However, no distinction is made between healthy and pathological tissue, which can cause undesired dam...

journal_title：Journal of medicinal chemistry

authors： Radunz S,Wedepohl S,Röhr M,Calderón M,Tschiche HR,Resch-Genger U

更新日期：2020-02-27 00:00:00

abstract：:Vacuolar type ATPase (V-ATPase) has recently emerged as a promising novel anticancer target based on extensive in vitro and in vivo studies with archazolids, complex polyketide macrolides, which present the most potent V-ATPase inhibitors known to date. Herein, we report a biomimetic, one-step preparation of archazoli...

journal_title：Journal of medicinal chemistry

authors： Scheeff S,Rivière S,Ruiz J,Abdelrahman A,Schulz-Fincke AC,Köse M,Tiburcy F,Wieczorek H,Gütschow M,Müller CE,Menche D

更新日期：2020-02-27 00:00:00

abstract：:Glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2) are proglucagon derived peptides that are released from gut endocrine cells in response to nutrient intake. These molecules are rapidly inactivated by the action of dipeptidyl peptidase IV (DPP-4) which limits their use as therapeutic agents. The rece...

journal_title：Journal of medicinal chemistry

authors： Suzuki R,Brown GA,Christopher JA,Scully CCG,Congreve M

更新日期：2020-02-13 00:00:00

abstract：:A series of derivatives of the antimycobacterial natural product pyridomycin have been prepared with the C2 side chain attached to the macrocyclic core structure by a C-C single bond, in place of the synthetically more demanding enol ester double bond found in the natural product. Hydrophobic C2 substituents of suffic...

journal_title：Journal of medicinal chemistry

authors： Kienle M,Eisenring P,Stoessel B,Horlacher OP,Hasler S,van Colen G,Hartkoorn RC,Vocat A,Cole ST,Altmann KH

更新日期：2020-02-13 00:00:00

abstract：:Dysregulation of translation initiation factor 4E (eIF4E) activity occurs in various cancers. Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) play a fundamental role in activation of eIF4E. Structure-activity relationship-driven expansion of a fragment hit led to discovery of dual M...

journal_title：Journal of medicinal chemistry

authors： Kwiatkowski J,Liu B,Pang S,Ahmad NHB,Wang G,Poulsen A,Yang H,Poh YR,Tee DHY,Ong E,Retna P,Dinie N,Kwek P,Wee JLK,Manoharan V,Low CB,Seah PG,Pendharkar V,Sangthongpitag K,Joy J,Baburajendran N,Jansson AE,Nacro

更新日期：2020-01-23 00:00:00

abstract：:Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt is conceptually new, unique for this specific nuclear receptor, and offers advantages over traditional orthosteric inhibition. Here, we report a highly...

journal_title：Journal of medicinal chemistry

authors： Meijer FA,Doveston RG,de Vries RMJM,Vos GM,Vos AAA,Leysen S,Scheepstra M,Ottmann C,Milroy LG,Brunsveld L

更新日期：2020-01-09 00:00:00

abstract：:ERAP1 is an endoplasmic reticulum-resident zinc aminopeptidase that plays an important role in the immune system by trimming peptides for loading onto major histocompatibility complex proteins. Here, we report discovery of the first inhibitors selective for ERAP1 over its paralogues ERAP2 and IRAP. Compound 1 (N-(N-(2...

journal_title：Journal of medicinal chemistry

authors： Maben Z,Arya R,Rane D,An WF,Metkar S,Hickey M,Bender S,Ali A,Nguyen TT,Evnouchidou I,Schilling R,Stratikos E,Golden J,Stern LJ

更新日期：2020-01-09 00:00:00

abstract：:Inherently conducting polymers (ICPs) are a specific category of synthetic polymers with distinctive electro-optic properties, which involve conjugated chains with alternating single and double bonds. Polyaniline (PANI), as one of the most well-known ICPs, has outstanding potential applications in biomedicine because ...

journal_title：Journal of medicinal chemistry

authors： Zare EN,Makvandi P,Ashtari B,Rossi F,Motahari A,Perale G

更新日期：2020-01-09 00:00:00

abstract：:Peptide modification with fatty acids is an effective method to improve peptide performance. We previously investigated the fatty acid modification of R-lycosin-I, a cytotoxic peptide derived from lycosin-I from the venom of the spider Lycosa singoriensis. In this study, we further investigated the position effects of...

journal_title：Journal of medicinal chemistry

authors： Zhang P,Jian C,Jian S,Zhang Q,Sun X,Nie L,Liu B,Li F,Li J,Liu M,Liang S,Zeng Y,Liu Z

更新日期：2019-12-26 00:00:00

abstract：:The cannabinoid type 2 (CB2) receptor has emerged as a valuable target for therapy and imaging of immune-mediated pathologies. With the aim to find a suitable radiofluorinated analogue of the previously reported CB2 positron emission tomography (PET) radioligand [11C]RSR-056, 38 fluorinated derivatives were synthesize...

journal_title：Journal of medicinal chemistry

authors： Haider A,Kretz J,Gobbi L,Ahmed H,Atz K,Bürkler M,Bartelmus C,Fingerle J,Guba W,Ullmer C,Honer M,Knuesel I,Weber M,Brink A,Herde AM,Keller C,Schibli R,Mu L,Grether U,Ametamey SM

更新日期：2019-12-26 00:00:00

abstract：:Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound 4, SLL-039) as a highly sele...

journal_title：Journal of medicinal chemistry

authors： Xiao L,Wang Y,Zhang M,Wu W,Kong L,Ma Y,Xu X,Liu X,He Q,Qian Y,Sun H,Wu H,Lin C,Huang H,Ye R,Jiang S,Ye RF,Yuan C,Fang S,Xue D,Yang X,Chen H,Zheng Y,Yu L,Xie Q,Zheng L,Fu W,Li W,Qiu Z,Liu J,Shao

更新日期：2019-12-26 00:00:00

abstract：:The NS2B/NS3 serine proteases of the Zika and Dengue flaviviruses are attractive targets for the development of antiviral drugs. We report the synthesis and evaluation of a new, proline-based compound class that displays allosteric inhibition of both proteases. The structural features relevant for protease binding and...

journal_title：Journal of medicinal chemistry

authors： Millies B,von Hammerstein F,Gellert A,Hammerschmidt S,Barthels F,Göppel U,Immerheiser M,Elgner F,Jung N,Basic M,Kersten C,Kiefer W,Bodem J,Hildt E,Windbergs M,Hellmich UA,Schirmeister T

更新日期：2019-12-26 00:00:00

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

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

abstract：:CC chemokine receptors 2 (CCR2) and 5 (CCR5) are involved in many inflammatory diseases; however, most CCR2 and CCR5 clinical candidates have been unsuccessful. (Pre)clinical evidence suggests that dual CCR2/CCR5 inhibition might be more effective in the treatment of such multifactorial diseases. In this regard, the h...

journal_title：Journal of medicinal chemistry

authors： Ortiz Zacarías NV,van Veldhoven JPD,den Hollander LS,Dogan B,Openy J,Hsiao YY,Lenselink EB,Heitman LH,IJzerman AP

更新日期：2019-12-26 00:00:00

abstract：:A series of nondimethylphenyl-diarylpyrimidines with much lower cytotoxicities than their dimethyl analogues were developed. Compound B13 with a difluorobiphenyl moiety showed the highest antiviral activity against WT, mutant strains, and RT. The hydrochloride form of B13 exhibited an improved water solubility of 5.6 ...

journal_title：Journal of medicinal chemistry

authors： Sang Y,Han S,Pannecouque C,De Clercq E,Zhuang C,Chen F

更新日期：2019-12-26 00:00:00

abstract：:Endosomal toll-like receptors (TLRs) 7 and 8 recognize viral single-stranded RNAs, a class of imidazoquinoline compounds, 8-oxo-adenosines, 8-aminobenzodiazepines, pyrimidines, and guanosine analogues. Substantial evidence is present linking chronic inflammation mediated specifically by TLR7 to the progression of auto...

journal_title：Journal of medicinal chemistry

authors： Padilla-Salinas R,Anderson R,Sakaniwa K,Zhang S,Nordeen P,Lu C,Shimizu T,Yin H

更新日期：2019-11-27 00:00:00

abstract：:Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that methylates nicotinamide (NAM) using cofactor S-adenosylmethionine (SAM). NNMT overexpression has been linked to diabetes, obesity, and various cancers. In this work, structure-based rational design led to the development of potent and selective alkynyl...

journal_title：Journal of medicinal chemistry

authors： Policarpo RL,Decultot L,May E,Kuzmič P,Carlson S,Huang D,Chu V,Wright BA,Dhakshinamoorthy S,Kannt A,Rani S,Dittakavi S,Panarese JD,Gaudet R,Shair MD

更新日期：2019-11-14 00:00:00

abstract：:Significant efforts have been reported on the development of influenza antivirals including inhibitors of the RNA-dependent RNA polymerase PA N-terminal (PAN) endonuclease. Based on recently identified, highly active metal-binding pharmacophores (MBPs) for PAN endonuclease inhibition, a fragment-based drug development...

journal_title：Journal of medicinal chemistry

authors： Credille CV,Morrison CN,Stokes RW,Dick BL,Feng Y,Sun J,Chen Y,Cohen SM

更新日期：2019-11-14 00:00:00

abstract：:We have derivatized Momordica saponins (MS) I and II through their coupling at C3 glucuronic acid site with dodecylamine. The derivatives show significantly different immunostimulant activity profiles from their respective natural parent saponins. In particular, adjuvant VSA-1 (5), the derivative of MS I, potentiates ...

journal_title：Journal of medicinal chemistry

authors： Wang P,Ding X,Kim H,Škalamera Đ,Michalek SM,Zhang P

更新日期：2019-11-14 00:00:00

abstract：:Proteasomes of pathogenic microbes have become attractive targets for anti-infectives. Coevolving with its human host, Mycobacterium tuberculosis (Mtb) has developed mechanisms to resist host-imposed nitrosative and oxidative stresses. Genetic deletion or pharmacological inhibition of the Mtb proteasome (Mtb20S) rende...

journal_title：Journal of medicinal chemistry

authors： Zhan W,Hsu HC,Morgan T,Ouellette T,Burns-Huang K,Hara R,Wright AG,Imaeda T,Okamoto R,Sato K,Michino M,Ramjee M,Aso K,Meinke PT,Foley M,Nathan CF,Li H,Lin G

更新日期：2019-10-24 00:00:00

abstract：:TYK2 is an emerging drug target for various human autoimmune diseases. However, discovery of selective TYK2 inhibitor over other JAK family members (i.e., JAK1, 2, 3) by targeting the catalytically active site (Janus Homologue 1 (JH1) domain) is challenging. This Viewpoint discusses the discovery of a series of N-meth...

journal_title：Journal of medicinal chemistry

authors： Chang Y,Xu S,Ding K

更新日期：2019-10-24 00:00:00

abstract：:By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective, and cell-activ...

journal_title：Journal of medicinal chemistry

authors： Xiong Y,Greschik H,Johansson C,Seifert L,Bacher J,Park KS,Babault N,Martini M,Fagan V,Li F,Chau I,Christott T,Dilworth D,Barsyte-Lovejoy D,Vedadi M,Arrowsmith CH,Brennan P,Fedorov O,Jung M,Farnie G,Liu J,Opperma

更新日期：2019-10-24 00:00:00

abstract：:Indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial and rate-limiting step of the kynurenine pathway of tryptophan catabolism, has emerged as a key target in cancer immunotherapy because of its role in enabling cancers to evade the immune system. Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxy...

journal_title：Journal of medicinal chemistry

authors： Yang D,Zhang S,Fang X,Guo L,Hu N,Guo Z,Li X,Yang S,He JC,Kuang C,Yang Q

更新日期：2019-10-24 00:00:00

abstract：:Low permeability across the outer membrane is a major reason why most antibiotics are ineffective against Gram-negative bacteria. Agents that permeabilize the outer membrane are typically toxic at their effective concentrations. Here, we report the development of a broad-spectrum homodimeric tobramycin adjuvant that i...

journal_title：Journal of medicinal chemistry

authors： Idowu T,Ammeter D,Rossong H,Zhanel GG,Schweizer F

更新日期：2019-10-24 00:00:00

abstract：:Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the rate-limiting step in the kynurenine pathway of tryptophan metabolism, which is involved in immunity, neuronal function, and aging. Its implication in pathologies such as cancer and neurodegenerative diseases has stimulated the development of IDO1 inhibitors. However,...

journal_title：Journal of medicinal chemistry

authors： Röhrig UF,Reynaud A,Majjigapu SR,Vogel P,Pojer F,Zoete V

更新日期：2019-10-10 00:00:00

abstract：:Short peptide-based inhibition of fusion remains an attractive goal in antihuman immunodeficiency virus (HIV) research based on its potential for the development of technically and economically desirable antiviral agents. Herein, we report the use of the dithiol bisalkylation reaction to generate a series of m-xylene ...

journal_title：Journal of medicinal chemistry

authors： Meng G,Pu J,Li Y,Han A,Tian Y,Xu W,Zhang T,Li X,Lu L,Wang C,Jiang S,Liu K

更新日期：2019-10-10 00:00:00

abstract：:Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-penta...

journal_title：Journal of medicinal chemistry

authors： Yamada S,Kawasaki M,Fujihara M,Watanabe M,Takamura Y,Takioku M,Nishioka H,Takeuchi Y,Makishima M,Motoyama T,Ito S,Tokiwa H,Nakano S,Kakuta H

更新日期：2019-10-10 00:00:00

abstract：:Dysfunction of monoacylglycerol lipase (MAGL) is associated with several psychopathological disorders, including drug addiction and neurodegenerative diseases. Herein we design, synthesize, and evaluate several irreversible fluorine-containing MAGL inhibitors for positron emission tomography (PET) ligand development. ...

journal_title：Journal of medicinal chemistry

authors： Chen Z,Mori W,Fu H,Schafroth MA,Hatori A,Shao T,Zhang G,Van RS,Zhang Y,Hu K,Fujinaga M,Wang L,Belov V,Ogasawara D,Giffenig P,Deng X,Rong J,Yu Q,Zhang X,Papisov MI,Shao Y,Collier TL,Ma JA,Cravatt BF,Josephs

更新日期：2019-10-10 00:00:00

abstract：:The mechanistic target of rapamycin (mTOR) plays a pivotal role in growth and tumor progression and is an attractive target for cancer treatment. ATP-competitive mTOR kinase inhibitors (TORKi) have the potential to overcome limitations of rapamycin derivatives in a wide range of malignancies. Herein, we exploit a conf...

journal_title：Journal of medicinal chemistry

authors： Borsari C,Rageot D,Dall'Asen A,Bohnacker T,Melone A,Sele AM,Jackson E,Langlois JB,Beaufils F,Hebeisen P,Fabbro D,Hillmann P,Wymann MP

更新日期：2019-09-26 00:00:00

abstract：:BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound 4 harboring a five-membered-ring linker motif, we quickly identified lead compound 7, which exhibited ...

journal_title：Journal of medicinal chemistry

authors： Hu J,Tian CQ,Damaneh MS,Li Y,Cao D,Lv K,Yu T,Meng T,Chen D,Wang X,Chen L,Li J,Song SS,Huan XJ,Qin L,Shen J,Wang YQ,Miao ZH,Xiong B

更新日期：2019-09-26 00:00:00

abstract：:A series of substituted 4,6-dihydrospiro[[1,2,3]triazolo[4,5-b]pyridine-7,3'-indoline]-2',5(3H)-dione analogues were synthesized and evaluated as potent dengue virus inhibitors. Throughout a structure-activity relationship exploration on the amide of the indolone moiety, a wide range of substitutions were found to be ...

journal_title：Journal of medicinal chemistry

authors： Xu J,Xie X,Ye N,Zou J,Chen H,White MA,Shi PY,Zhou J

更新日期：2019-09-12 00:00:00

abstract：:Transient receptor potential canonical (TRPC) channels are highly homologous, nonselective cation channels that form many homo- and heterotetrameric channels. These channels are highly abundant in the brain and kidney and have been implicated in numerous diseases, such as depression, addiction, and chronic kidney dise...

journal_title：Journal of medicinal chemistry

authors： Sharma S,Hopkins CR

更新日期：2019-09-12 00:00:00

abstract：:Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in ac...

journal_title：Journal of medicinal chemistry

authors： Whitehouse AJ,Thomas SE,Brown KP,Fanourakis A,Chan DS,Libardo MDJ,Mendes V,Boshoff HIM,Floto RA,Abell C,Blundell TL,Coyne AG

更新日期：2019-08-08 00:00:00

abstract：:Tertiary EGFRC797S mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFRL858R/T790M/C797S inhibitors. A representative compound, 8r-B,...

journal_title：Journal of medicinal chemistry

authors： Shen J,Zhang T,Zhu SJ,Sun M,Tong L,Lai M,Zhang R,Xu W,Wu R,Ding J,Yun CH,Xie H,Lu X,Ding K

更新日期：2019-08-08 00:00:00

abstract：:Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers...

journal_title：Journal of medicinal chemistry

authors： Finlay MRV,Anderton M,Bailey A,Boyd S,Brookfield J,Cairnduff C,Charles M,Cheasty A,Critchlow SE,Culshaw J,Ekwuru T,Hollingsworth I,Jones N,Leroux F,Littleson M,McCarron H,McKelvie J,Mooney L,Nissink JWM,Perkins D,

更新日期：2019-07-25 00:00:00

abstract：:Recruitment of suppressive CD4+ FOXP3+ regulatory T cells (Treg) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human Treg express CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CC...

journal_title：Journal of medicinal chemistry

authors： Jackson JJ,Ketcham JM,Younai A,Abraham B,Biannic B,Beck HP,Bui MHT,Chian D,Cutler G,Diokno R,Hu DX,Jacobson S,Karbarz E,Kassner PD,Marshall L,McKinnell J,Meleza C,Okal A,Pookot D,Reilly MK,Robles O,Shunatona HP

更新日期：2019-07-11 00:00:00

abstract：:Inhibition of the menin-mixed lineage leukemia (MLL) protein-protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the me...

journal_title：Journal of medicinal chemistry

authors： Aguilar A,Zheng K,Xu T,Xu S,Huang L,Fernandez-Salas E,Liu L,Bernard D,Harvey KP,Foster C,McEachern D,Stuckey J,Chinnaswamy K,Delproposto J,Kampf JW,Wang S

更新日期：2019-07-11 00:00:00

abstract：:A series of pyrazolopyrimidine inhibitors of IRAK4 were developed from a high-throughput screen (HTS). Modification of an HTS hit led to a series of bicyclic heterocycles with improved potency and kinase selectivity but lacking sufficient solubility to progress in vivo. Structure-based drug design, informed by cocryst...

journal_title：Journal of medicinal chemistry

authors： Bryan MC,Drobnick J,Gobbi A,Kolesnikov A,Chen Y,Rajapaksa N,Ndubaku C,Feng J,Chang W,Francis R,Yu C,Choo EF,DeMent K,Ran Y,An L,Emson C,Huang Z,Sujatha-Bhaskar S,Brightbill H,DiPasquale A,Maher J,Wai J,McKenzi

更新日期：2019-07-11 00:00:00

abstract：:As the number of cases and cancer-related deaths are projected to rise in upcoming years, it is urgent to find ways to prevent or treat cancer. As such, food-derived products have gained attention as potential chemopreventive agents due to their availability, safety, and low cost. Isothiocyanates, the breakdown produc...

journal_title：Journal of medicinal chemistry

authors： Frieben EE,Amin S,Sharma AK

更新日期：2019-06-13 00:00:00

abstract：:The use of deuteration in medicinal chemistry has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms...

journal_title：Journal of medicinal chemistry

authors： Pirali T,Serafini M,Cargnin S,Genazzani AA

更新日期：2019-06-13 00:00:00