The Dark Side of Fluorine.

abstract：:With only two new classes of antibiotics developed in the last 40 years, novel antibiotics are desperately needed to combat the growing problem of multidrug-resistant and extensively drug resistant bacteria, particularly Gram-negative bacteria. Described in this letter is the synthesis and antibiotic activity of 1,2,4...

journal_title：ACS medicinal chemistry letters

authors： Huggins WM,Minrovic BM,Corey BW,Jacobs AC,Melander RJ,Sommer RD,Zurawski DV,Melander C

更新日期：2016-11-12 00:00:00

abstract：:SMARTCyp is an in silico method that predicts the sites of cytochrome P450-mediated metabolism of druglike molecules. The method is foremost a reactivity model, and as such, it shows a preference for predicting sites that are metabolized by the cytochrome P450 3A4 isoform. SMARTCyp predicts the site of metabolism dire...

journal_title：ACS medicinal chemistry letters

authors： Rydberg P,Gloriam DE,Zaretzki J,Breneman C,Olsen L

更新日期：2010-03-15 00:00:00

abstract：:1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate isoprene biosynthesis pathway is a target for developing antimalarial drugs. Fosmidomycin, a potent DXR inhibitor, showed safety as well as efficacy against P. falciparum malaria in clinical trials. Based on our previous quantitative structure...

journal_title：ACS medicinal chemistry letters

authors： Xue J,Diao J,Cai G,Deng L,Zheng B,Yao Y,Song Y

更新日期：2013-02-14 00:00:00

abstract：:This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization leading to the identification, characterization, and pharmacologica...

journal_title：ACS medicinal chemistry letters

authors： Jin M,Gokhale PC,Cooke A,Foreman K,Buck E,May EW,Feng L,Bittner MA,Kadalbajoo M,Landfair D,Siu KW,Stolz KM,Werner DS,Laufer RS,Li AH,Dong H,Steinig AG,Kleinberg A,Yao Y,Pachter JA,Wild R,Mulvihill MJ

更新日期：2010-08-30 00:00:00

abstract：:Retinoid X receptor-alpha (RXRα) is implicated in the regulation of many biological processes and also represents a unique intracellular target for pharmacologic interventions. Efforts on discovery of small molecules targeting RXRα have been primarily focused on the molecules that bind to its classical ligand-binding ...

journal_title：ACS medicinal chemistry letters

authors： Chen F,Liu J,Huang M,Hu M,Su Y,Zhang XK

更新日期：2014-05-14 00:00:00

abstract：:The polyether ionophore salinomycin has recently gained attention due to its exceptional ability to selectively reduce the proportion of cancer stem cells within a number of cancer cell lines. Efficient single step strategies for the preparation of hydroxamic acid hybrids of this compound varying in N- and O-alkylatio...

journal_title：ACS medicinal chemistry letters

authors： Borgström B,Huang X,Chygorin E,Oredsson S,Strand D

更新日期：2016-04-25 00:00:00

abstract：:Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. T...

journal_title：ACS medicinal chemistry letters

authors： Kallander LS,Washburn D,Hilfiker MA,Eidam HS,Lawhorn BG,Prendergast J,Fox R,Dowdell S,Manns S,Hoang T,Zhao S,Ye G,Hammond M,Holt DA,Roethke T,Hong X,Reid RA,Gampe R,Zhang H,Diaz E,Rendina AR,Quinn AM,Willette

更新日期：2018-07-02 00:00:00

abstract：:Fluorescent biosensors constitute potent tools for probing biomolecules in their natural environment and for visualizing dynamic processes in complex biological samples, living cells, and organisms. They are well suited for highlighting molecular alterations associated with pathological disorders, thereby offering mea...

journal_title：ACS medicinal chemistry letters

authors： Morris MC

更新日期：2013-12-18 00:00:00

abstract：:Organophosphorus nerve agents (OPNAs) inhibit acetylcholinesterase (AChE) and, despite the Chemical Weapons Convention arms control treaty, continue to represent a threat to both military personnel and civilians. 2-Pralidoxime (2-PAM) is currently the only therapeutic countermeasure approved by the United States Food ...

journal_title：ACS medicinal chemistry letters

authors： Gambino A,Burnett JC,Koide K

更新日期：2020-01-09 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：:To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists ...

journal_title：ACS medicinal chemistry letters

authors： Ogawa S,Watanabe T,Sugimoto I,Moriyuki K,Goto Y,Yamane S,Watanabe A,Tsuboi K,Kinoshita A,Kigoshi H,Tani K,Maruyama T

更新日期：2016-01-04 00:00:00

abstract：:A new series of 1,4-naphthoquinones, bearing various cyclic and aliphatic amines on C2, was designed and synthesized to identify antiproliferative agents for triple-negative breast cancer, which represents a clinical challenge without targeted therapies. Among naphthoquinones, 2a and 3a inhibited the proliferation of ...

journal_title：ACS medicinal chemistry letters

authors： Badolato M,Carullo G,Caroleo MC,Cione E,Aiello F,Manetti F

更新日期：2019-02-15 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 protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interact...

journal_title：ACS medicinal chemistry letters

authors： Millan DS,Kayser-Bricker KJ,Martin MW,Talbot AC,Schiller SER,Herbertz T,Williams GL,Luke GP,Hubbs S,Alvarez Morales MA,Cardillo D,Troccolo P,Mendes RL,McKinnon C

更新日期：2017-07-14 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：:The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be n...

journal_title：ACS medicinal chemistry letters

authors： Goodwin NC,Cianchetta G,Burgoon HA,Healy J,Mabon R,Strobel ED,Allen J,Wang S,Hamman BD,Rawlins DB

更新日期：2014-08-07 00:00:00

abstract：:Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor α2β1 antagonists were developed. The amino acid derived low molecular weight 14-18-membered macrocycles turned out to be highly active toward integrin α2β1 with IC50s in the low nanomolar r...

journal_title：ACS medicinal chemistry letters

authors： Halland N,Blum H,Buning C,Kohlmann M,Lindenschmidt A

更新日期：2014-01-10 00:00:00

abstract：:PROTACs-induced targeted protein degradation has emerged as a novel therapeutic strategy in drug development and attracted the favor of academic institutions, large pharmaceutical enterprises (e.g., AstraZeneca, Bayer, Novartis, Amgen, Pfizer, GlaxoSmithKline, Merck, and Boehringer Ingelheim, etc.), and biotechnology ...

journal_title：ACS medicinal chemistry letters

authors： Gao H,Sun X,Rao Y

更新日期：2020-03-12 00:00:00

abstract：:A competitive fluorescence polarization (FP) assay is reported for determining binding affinities of probe molecules with the pseudokinase JAK2 JH2 allosteric site. The syntheses of the fluorescent 5 and 6 used in the assay are reported as well as Kd results for 10 compounds, including JNJ7706621, NVP-BSK805, and filg...

journal_title：ACS medicinal chemistry letters

authors： Newton AS,Deiana L,Puleo DE,Cisneros JA,Cutrona KJ,Schlessinger J,Jorgensen WL

更新日期：2017-05-17 00:00:00

abstract：:A number of biologically active nucleoside analogues contain the adenine isostere 4-amino-pyrrolo[2,1-f][1,2,4]triazine connected to various sugar moieties through a C-C anomeric linkage. We employed palladium-catalyzed cross-coupling chemistry to promptly functionalize the 7-position of such a heterocyclic scaffold w...

journal_title：ACS medicinal chemistry letters

authors： Li Q,Groaz E,Persoons L,Daelemans D,Herdewijn P

更新日期：2020-07-09 00:00:00

abstract：:We describe the discovery of three structurally differentiated potent and selective MTH1 inhibitors and their subsequent use to investigate MTH1 as an oncology target, culminating in target (in)validation. Tetrahydronaphthyridine 5 was rapidly identified as a highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystalli...

journal_title：ACS medicinal chemistry letters

authors： Farand J,Kropf JE,Blomgren P,Xu J,Schmitt AC,Newby ZE,Wang T,Murakami E,Barauskas O,Sudhamsu J,Feng JY,Niedziela-Majka A,Schultz BE,Schwartz K,Viatchenko-Karpinski S,Kornyeyev D,Kashishian A,Fan P,Chen X,Lansdon EB

更新日期：2019-11-19 00:00:00

abstract：:The discovery and characterization of two classes of kappa opioid receptor agonists that are biased for G protein over βarrestin signaling are described. ...

journal_title：ACS medicinal chemistry letters

authors： Bohn LM,Aubé J

更新日期：2017-07-05 00:00:00

abstract：:Cellular proteins that fail to fold properly result in inactive or disfunctional proteins that can have toxic functions. The unfolded protein response (UPR) is a two-tiered cellular mechanism initiated by eukaryotic cells that have accumulated misfolded proteins within the endoplasmic reticulum (ER). An adaptive pathw...

journal_title：ACS medicinal chemistry letters

authors： Flaherty DP,Miller JR,Garshott DM,Hedrick M,Gosalia P,Li Y,Milewski M,Sugarman E,Vasile S,Salaniwal S,Su Y,Smith LH,Chung TD,Pinkerton AB,Aubé J,Callaghan MU,Golden JE,Fribley AM,Kaufman RJ

更新日期：2014-10-29 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：:Highly toxic bacterial ionophores are commonly used in veterinary medicine, but their therapeutic index is too narrow for human usage. With the goal of developing ionophores with a broader therapeutic index, we constructed highly derivatized synthetic ionophores. The toxicities of crown ether host-rotaxanes (CEHR's) a...

journal_title：ACS medicinal chemistry letters

authors： Smithrud DB,Wang X,Tarapore P,Ho SM

更新日期：2013-01-10 00:00:00

abstract：:Neuromedin U (NMU) and S (NMS) display various physiological activities, including an anorexigenic effect, and share a common C-terminal heptapeptide-amide sequence that is necessary to activate two NMU receptors (NMUR1 and NMUR2). On the basis of this knowledge, we recently developed hexapeptide agonists 2 and 3, whi...

journal_title：ACS medicinal chemistry letters

authors： Takayama K,Mori K,Sohma Y,Taketa K,Taguchi A,Yakushiji F,Minamino N,Miyazato M,Kangawa K,Hayashi Y

更新日期：2015-01-28 00:00:00

abstract：:Stable isotope-mass spectrometry (MS)-based metabolomic profiling is a powerful technique for following changes in specific metabolite pool sizes and metabolic flux under various experimental conditions in a test organism or cell type. Here, we use a metabolomics approach to interrogate the mechanism of antibiotic act...

journal_title：ACS medicinal chemistry letters

authors： Prosser GA,de Carvalho LP

更新日期：2013-12-12 00:00:00

abstract：:The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca2+ and Na+. NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recentl...

journal_title：ACS medicinal chemistry letters

authors： Villemure E,Volgraf M,Jiang Y,Wu G,Ly CQ,Yuen PW,Lu A,Luo X,Liu M,Zhang S,Lupardus PJ,Wallweber HJ,Liederer BM,Deshmukh G,Plise E,Tay S,Wang TM,Hanson JE,Hackos DH,Scearce-Levie K,Schwarz JB,Sellers BD

更新日期：2016-10-31 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：:A new prosthetic group referred to as the triazole appending agent (TAAG) was developed as a means to prepare targeted radioiodine-based molecular imaging and therapy agents. Tributyltin-TAAG and the fluorous analogue were synthesized in high yield using simple click chemistry and the products labeled in greater than ...

journal_title：ACS medicinal chemistry letters

authors： Darwish A,Blacker M,Janzen N,Rathmann SM,Czorny S,Hillier SM,Joyal JL,Babich JW,Valliant JF

更新日期：2012-02-18 00:00:00