Design and Synthesis of 2-Alkylpyrimidine-4,6-diol and 6-Alkylpyridine-2,4-diol as Potent GPR84 Agonists.

abstract：:A series of fluorine-substituted monomeric and dimeric cRGD peptide derivatives, such as cRGD-ADIBOT-F (ADIBOT = azadibenzocyclooctatriazole), di-cRGD-ADIBOT-F, cRGD-PEG5-ADIBOT-F, and di-cRGD-PEG5-ADIBOT-F, were prepared by strain-promoted alkyne azide cycloaddition (SPAAC) reaction of the corresponding aza-dibenzocy...

journal_title：ACS medicinal chemistry letters

authors： Kim HL,Sachin K,Jeong HJ,Choi W,Lee HS,Kim DW

更新日期：2015-02-06 00:00:00

abstract：:Specific abrogation of cyclin-dependent kinase 5 (CDK5) activity has been validated as a viable approach for the development of anticancer agents. However, no selective CDK5 inhibitor has been reported to date. Herein, a structure-based in silico screening was employed to identify novel scaffolds from a library of com...

journal_title：ACS medicinal chemistry letters

authors： Khair NZ,Lenjisa JL,Tadesse S,Kumarasiri M,Basnet SKC,Mekonnen LB,Li M,Diab S,Sykes MJ,Albrecht H,Milne R,Wang S

更新日期：2019-03-20 00:00:00

abstract：:This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described. ...

journal_title：ACS medicinal chemistry letters

authors： Miller CP,Shomali M,Lyttle CR,O'Dea LS,Herendeen H,Gallacher K,Paquin D,Compton DR,Sahoo B,Kerrigan SA,Burge MS,Nickels M,Green JL,Katzenellenbogen JA,Tchesnokov A,Hattersley G

更新日期：2010-12-02 00:00:00

abstract：:An original design and synthesis of fluorescent ligands for melatonin receptor studies is presented and consists in the fusion of the endogenous ligand with the fluorescent BODIPY core. Probes I-IV show high affinities for MT1 and MT2 melatonin receptors and exhibit fluorescence properties compatible with cell observa...

journal_title：ACS medicinal chemistry letters

authors： Thireau J,Marteaux J,Delagrange P,Lefoulon F,Dufourny L,Guillaumet G,Suzenet F

更新日期：2013-11-20 00:00:00

abstract：:We describe the synthesis and SAR studies of divin-a small molecule that blocks bacterial division by perturbing the assembly of proteins at the site of cell septation. The bacteriostatic mechanism of action of divin is distinct from other reported inhibitors of bacterial cell division and provides an opportunity for ...

journal_title：ACS medicinal chemistry letters

authors： Zhou M,Eun YJ,Guzei IA,Weibel DB

更新日期：2013-09-12 00:00:00

abstract：:C646 inhibits the lysine acetyltransferases (KATs) p300 and CBP and represents the most potent and selective small molecule KAT inhibitor identified to date. To gain insights into the cellular activity of this epigenetic probe, we applied chemoproteomics to identify covalent targets of the C646 chemotype. Modeling and...

journal_title：ACS medicinal chemistry letters

authors： Shrimp JH,Sorum AW,Garlick JM,Guasch L,Nicklaus MC,Meier JL

更新日期：2015-10-31 00:00:00

abstract：:Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties and a mixed m...

journal_title：ACS medicinal chemistry letters

authors： Stepan AF,Tran TP,Helal CJ,Brown MS,Chang C,O'Connor RE,De Vivo M,Doran SD,Fisher EL,Jenkinson S,Karanian D,Kormos BL,Sharma R,Walker GS,Wright AS,Yang EX,Brodney MA,Wager TT,Verhoest PR,Obach RS

更新日期：2018-01-04 00:00:00

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

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

abstract：:In light of the biomedical significance of metallo-β-lactamases (MβLs), ten new mercaptoacetic acid thioester amino acid derivatives were synthesized and characterized. Biological activity assays indicated that all these synthesized compounds are very potent inhibitors of L1, exhibiting an IC50 value range of 0.018-2....

journal_title：ACS medicinal chemistry letters

authors： Liu XL,Shi Y,Kang JS,Oelschlaeger P,Yang KW

更新日期：2015-04-23 00:00:00

abstract：:Compound libraries provide a starting point for multiple biological investigations, but the structural integrity of compounds is rarely assessed experimentally until a late stage in the research process. Here, we describe the discovery of a neuroprotective small molecule that was originally incorrectly annotated with ...

journal_title：ACS medicinal chemistry letters

authors： Kaplan A,Stockwell BR

更新日期：2015-07-29 00:00:00

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

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

abstract：:The multistep preparation of (11)C-levetiracetam ((11)C-LEV) was carried out by a one-pot radiosynthesis with 8.3 ± 1.6% (n = 8) radiochemical yield in 50 ± 5.0 min. Briefly, the propionaldehyde was converted to propan-1-imine in situ as labeling precursor by incubation with ammonia. Without further separation, the im...

journal_title：ACS medicinal chemistry letters

authors： Cai H,Mangner TJ,Muzik O,Wang MW,Chugani DC,Chugani HT

更新日期：2014-08-19 00:00:00

abstract：:The identification and optimization of the first activators of fast skeletal muscle are reported. Compound 1 was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of 1 for potency, metabolic stability, and physical ...

journal_title：ACS medicinal chemistry letters

authors： Collibee SE,Bergnes G,Muci A,Browne WF 4th,Garard M,Hinken AC,Russell AJ,Suehiro I,Hartman J,Kawas R,Lu PP,Lee KH,Marquez D,Tomlinson M,Xu D,Kennedy A,Hwee D,Schaletzky J,Leung K,Malik FI,Morgans DJ Jr,Morgan BP

更新日期：2018-02-13 00:00:00

abstract：:GPR40 is a G-protein-coupled receptor which mediates fatty acid-induced glucose-stimulated insulin secretion from pancreatic beta cells and incretion release from enteroendocrine cells of the small intestine. GPR40 full agonists exhibit superior glucose lowering compared to partial agonists in preclinical species due ...

journal_title：ACS medicinal chemistry letters

authors： Huang H,Meegalla SK,Lanter JC,Winters MP,Zhao S,Littrell J,Qi J,Rady B,Lee PS,Liu J,Martin T,Lam WW,Xu F,Lim HK,Wilde T,Silva J,Otieno M,Pocai A,Player MR

更新日期：2018-12-03 00:00:00

abstract：:The atypical chemokine receptor CXCR7 has been studied in various disease settings including immunological diseases and heart disease. Efforts to elucidate the role of CXCR7 have been limited by the lack of suitable chemical tools with a range of pharmacological profiles. A high-throughput screen was conducted to disc...

journal_title：ACS medicinal chemistry letters

authors： Menhaji-Klotz E,Ward J,Brown JA,Loria PM,Tan C,Hesp KD,Riccardi KA,Litchfield J,Boehm M

更新日期：2020-05-14 00:00:00

abstract：:We report the design, synthesis, and biological evaluation of a (64)Cu-labeled histone deacetylase (HDAC) imaging probe, which was obtained by introduction of metal chelator through click reaction of HDAC inhibitor CUDC-101 and then radiolabeled with (64)Cu. The resulting (64)Cu-labeled compound 7 ([(64)Cu]7) was iden...

journal_title：ACS medicinal chemistry letters

authors： Meng Q,Li F,Jiang S,Li Z

更新日期：2013-07-25 00:00:00

abstract：:EPAC proteins are therapeutic targets for the potential treatment of cardiac hypertrophy and cancer metastasis. Several laboratories use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1 in various disease states. Here, we report SAR studies with tetrahydroquinoline analogs that explore various functio...

journal_title：ACS medicinal chemistry letters

authors： Sonawane YA,Zhu Y,Garrison JC,Ezell EL,Zahid M,Cheng X,Natarajan A

更新日期：2017-10-02 00:00:00

abstract：:Herein, we report the structure-activity relationships within a series of mGlu7 PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (Kps > 1 and Kp,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu...

journal_title：ACS medicinal chemistry letters

authors： Abe M,Seto M,Gogliotti RG,Loch MT,Bollinger KA,Chang S,Engelberg EM,Luscombe VB,Harp JM,Bubser M,Engers DW,Jones CK,Rodriguez AL,Blobaum AL,Conn PJ,Niswender CM,Lindsley CW

更新日期：2017-09-01 00:00:00

abstract：:Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood-brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules...

journal_title：ACS medicinal chemistry letters

authors： Heffron TP,Ndubaku CO,Salphati L,Alicke B,Cheong J,Drobnick J,Edgar K,Gould SE,Lee LB,Lesnick JD,Lewis C,Nonomiya J,Pang J,Plise EG,Sideris S,Wallin J,Wang L,Zhang X,Olivero AG

更新日期：2016-02-16 00:00:00

abstract：:A new series of potent TG2 inhibitors are reported that employ a 4-aminopiperidine core bearing an acrylamide warhead. We establish the structure-activity relationship of this new series and report on the transglutaminase selectivity and in vitro ADME properties of selected compounds. We demonstrate that the compounds...

journal_title：ACS medicinal chemistry letters

authors： Prime ME,Brookfield FA,Courtney SM,Gaines S,Marston RW,Ichihara O,Li M,Vaidya D,Williams H,Pedret-Dunn A,Reed L,Schaertl S,Toledo-Sherman L,Beconi M,Macdonald D,Muñoz-Sanjuan I,Dominguez C,Wityak J

更新日期：2012-08-09 00:00:00

abstract：:The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORγt with 1a, an analogue of the known pip...

journal_title：ACS medicinal chemistry letters

authors： Nakajima R,Oono H,Sugiyama S,Matsueda Y,Ida T,Kakuda S,Hirata J,Baba A,Makino A,Matsuyama R,White RD,Wurz RΡ,Shin Y,Min X,Guzman-Perez A,Wang Z,Symons A,Singh SK,Mothe SR,Belyakov S,Chakrabarti A,Shuto S

更新日期：2020-02-27 00:00:00

abstract：:A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overc...

journal_title：ACS medicinal chemistry letters

authors： Huang X,Brubaker J,Zhou W,Biju PJ,Xiao L,Shao N,Huang Y,Dong L,Liu Z,Bitar R,Buevich A,Jung J,Peterson SL,Butcher JW,Close J,Martinez M,MacCoss RN,Zhang H,Crawford S,McCormick KD,Aslanian R,Nargund R,Correll C

更新日期：2018-06-23 00:00:00

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

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

更新日期：2012-08-28 00:00:00

abstract：:Purine-rich foods have long been suspected as a major cause of hyperuricemia. We hypothesized that inhibition of human concentrative nucleoside transporter 2 (hCNT2) would suppress increases in serum urate levels derived from dietary purines. To test this hypothesis, the development of potent hCNT2 inhibitors was requ...

journal_title：ACS medicinal chemistry letters

authors： Tatani K,Hiratochi M,Nonaka Y,Isaji M,Shuto S

更新日期：2015-01-28 00:00:00

abstract：:The receptor for the neuropeptide relaxin 3, relaxin family peptide 3 (RXFP3) receptor, is an attractive pharmacological target for the control of eating, addictive, and psychiatric behaviors. Several structure-activity relationship studies on both human relaxin 3 (containing 3 disulfide bonds) and its analogue A2 (tw...

journal_title：ACS medicinal chemistry letters

authors： Praveen P,Tailhades J,Rosengren KJ,Liu M,Wade JD,Bathgate RAD,Hossain MA

更新日期：2020-10-22 00:00:00

abstract：:A novel modulator of sodium ion currents was synthesized in 6 steps from a protected dihydroxypyrrolidine nitrone, via 1,3-dipolar cycloaddition reaction with acrylamide. Sodium ion currents in B50 cells were evaluated in comparison to saxitoxin and tetrodotoxin, and revealed an IC(50) of 15.7 muM. The new compound sh...

journal_title：ACS medicinal chemistry letters

authors： Mao H,Fieber LA,Gawley RE

更新日期：2010-03-31 00:00:00

abstract：:Dipeptidyl nitroalkenes are potent reversible inhibitors of cysteine proteases. Inhibitor 11 resulted to be the most potent one with Ki values of 0.49 and 0.44 nM against rhodesain and cruzain, respectively. According to enzymatic dilution and dialysis experiments, as well as computational and NMR studies, dipeptidyl ...

journal_title：ACS medicinal chemistry letters

authors： Latorre A,Schirmeister T,Kesselring J,Jung S,Johé P,Hellmich UA,Heilos A,Engels B,Krauth-Siegel RL,Dirdjaja N,Bou-Iserte L,Rodríguez S,González FV

更新日期：2016-09-21 00:00:00

abstract：:Tankyrases, an enzyme subfamily of human poly(ADP-ribosyl)polymerases, are potential drug targets especially against cancer. We have evaluated inhibition of tankyrases by known PARP inhibitors and report five cocrystal structures of the most potent compounds in complex with human tankyrase 2. The inhibitors include th...

journal_title：ACS medicinal chemistry letters

authors： Haikarainen T,Narwal M,Joensuu P,Lehtiö L

更新日期：2013-11-20 00:00:00

abstract：:The BRPF (bromodomain and PHD finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Here, we report the discovery, binding mode, and structure-activity relationship (SAR) of the first potent, selective series of inhibitors of the BRPF1 bromodomai...

journal_title：ACS medicinal chemistry letters

authors： Demont EH,Bamborough P,Chung CW,Craggs PD,Fallon D,Gordon LJ,Grandi P,Hobbs CI,Hussain J,Jones EJ,Le Gall A,Michon AM,Mitchell DJ,Prinjha RK,Roberts AD,Sheppard RJ,Watson RJ

更新日期：2014-09-10 00:00:00

abstract：:Approximately 1.7 million Americans develop hospital associated infections each year, resulting in more than 98,000 deaths. One of the main contributors to such infections is the Gram-negative pathogen Acinetobacter baumannii. Recently, it was reported that aryl 2-aminoimidazole (2-AI) compounds potentiate macrolide a...

journal_title：ACS medicinal chemistry letters

authors： Hubble VB,Bartholomew KR,Weig AW,Brackett SM,Barlock SL,Mattingly AE,Nemeth AM,Melander RJ,Melander C

更新日期：2020-08-12 00:00:00