Structure-Guided Optimization of Replication Protein A (RPA)-DNA Interaction Inhibitors.

abstract：:We report here the total synthesis of B-973 (five steps), a recently identified α7 nAChR ago-PAM, its enantiomeric resolution, and its electrophysiological characterization in Xenopus oocytes to identify (-)-B-973B as the bioactive enantiomer. The asymmetric synthesis of B-973B was accomplished in 99% ee, and X-ray cr...

journal_title：ACS medicinal chemistry letters

authors： Garai S,Raja KS,Papke RL,Deschamps JR,Damaj MI,Thakur GA

更新日期：2018-10-11 00:00:00

abstract：:Minibodies show rapider blood clearance than IgGs due to smaller size that improves target-to-background ratio (TBR) in in vivo imaging. Additionally, the ability to activate an optical probe after binding to the target greatly improves the TBR. An optical imaging probe based on a minibody against prostate-specific me...

journal_title：ACS medicinal chemistry letters

authors： Watanabe R,Sato K,Hanaoka H,Harada T,Nakajima T,Kim I,Paik CH,Wu AM,Choyke PL,Kobayashi H

更新日期：2014-01-17 00:00:00

abstract：:We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in v...

journal_title：ACS medicinal chemistry letters

authors： Chobanian HR,Guo Y,Liu P,Chioda MD,Fung S,Lanza TJ,Chang L,Bakshi RK,Dellureficio JP,Hong Q,McLaughlin M,Belyk KM,Krska SW,Makarewicz AK,Martel EJ,Leone JF,Frey L,Karanam B,Madeira M,Alvaro R,Shuman J,Salituro G

更新日期：2014-04-10 00:00:00

abstract：:We have employed novel fragment-based screening methodology to discover bivalent kinase inhibitors with improved selectivity. Starting from a low molecular weight promiscuous kinase inhibitor, we appended a thiol for subsequent reaction with a library of acrylamide electrophiles. Enzyme-templated screening was perform...

journal_title：ACS medicinal chemistry letters

authors： Kwarcinski FE,Steffey ME,Fox CC,Soellner MB

更新日期：2015-07-13 00:00:00

abstract：:The design, synthesis, biological evaluation, and X-ray structural studies are reported for a series of highly potent HIV-1 protease inhibitors. The inhibitors incorporated stereochemically defined amide-based bicyclic and tricyclic ether derivatives as the P2 ligands with (R)-hydroxyethylaminesulfonamide transition-s...

journal_title：ACS medicinal chemistry letters

authors： Ghosh AK,Grillo A,Raghavaiah J,Kovela S,Johnson ME,Kneller DW,Wang YF,Hattori SI,Higashi-Kuwata N,Weber IT,Mitsuya H

更新日期：2020-03-03 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：:Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing the undesira...

journal_title：ACS medicinal chemistry letters

authors： Johnson DS,Stiff C,Lazerwith SE,Kesten SR,Fay LK,Morris M,Beidler D,Liimatta MB,Smith SE,Dudley DT,Sadagopan N,Bhattachar SN,Kesten SJ,Nomanbhoy TK,Cravatt BF,Ahn K

更新日期：2011-02-10 00:00:00

abstract：:A new class of potent matrix metalloproteinase (MMP) inhibitors designed by structure-based optimization of the well-known arylsulfonamide scaffold is presented. Molecules show an ethylene linker connecting the sulfonamide group with the P1' aromatic portion and a d-proline residue bearing the zinc-binding group. The ...

journal_title：ACS medicinal chemistry letters

authors： Mori M,Massaro A,Calderone V,Fragai M,Luchinat C,Mordini A

更新日期：2013-05-14 00:00:00

abstract：:Rapid detection and precise evaluation of myocardial viability is necessary to aid in clinical decision making whether to recommend revascularization for patients with myocardial infarction (MI). Three novel 18F-labeled 1-hydroxyanthraquinone derivatives were synthesized, characterized, and evaluated as potential necr...

journal_title：ACS medicinal chemistry letters

authors： Ji AY,Jin QM,Zhang DJ,Zhu H,Su C,Duan XH,Bian L,Sun ZP,Ni YC,Zhang J,Yang Z,Yin ZQ

更新日期：2016-12-28 00:00:00

abstract：:Ataluren was reported to suppress nonsense mutations by promoting the readthrough of premature stop codons, although its mechanism of action (MOA) is still debated. The likely interaction of Ataluren with CFTR-mRNA has been previously studied by molecular dynamics. In this work we extended the modeling of Ataluren's M...

journal_title：ACS medicinal chemistry letters

authors： Tutone M,Pibiri I,Lentini L,Pace A,Almerico AM

更新日期：2019-02-07 00:00:00

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：:Synthesis of a strict structural analogue of albaconazole in which the quinazolinone ring is fused by a thiazole moiety led to the discovery of a new triazole with broad-spectrum antifungal activity. Compound I exhibited high in vitro activity against pathogenic Candida species and filamentous fungi and showed prelimi...

journal_title：ACS medicinal chemistry letters

authors： Guillon R,Pagniez F,Picot C,Hédou D,Tonnerre A,Chosson E,Duflos M,Besson T,Logé C,Le Pape P

更新日期：2013-01-17 00:00:00

abstract：:A series of novel N-acyclic uracil analogs with linear, branched, aromatic, and cyclopropyl-alkynyl as well as heteroaryl moieties at C-5 were prepared using palladium catalyzed Sonogashira and Stille cross-coupling and evaluated against malignant tumor cell lines. C-5-Furan-2-yl uracil derivative 6 was shown to be mo...

journal_title：ACS medicinal chemistry letters

authors： Meščić A,Harej A,Klobučar M,Glavač D,Cetina M,Pavelić SK,Raić-Malić S

更新日期：2015-10-05 00:00:00

abstract：:Toxoplasma gondii causes a prevalent human infection for which only the acute stage has an FDA-approved therapy. To find inhibitors of both the acute stage parasites and the persistent cyst stage that causes a chronic infection, we repurposed a compound library containing known inhibitors of parasitic hexokinase, the ...

journal_title：ACS medicinal chemistry letters

authors： Khalifa MM,Martorelli Di Genova B,McAlpine SG,Gallego-Lopez GM,Stevenson DM,Rozema SD,Monaghan NP,Morris JC,Knoll LJ,Golden JE

更新日期：2020-10-13 00:00:00

abstract：:The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization ...

journal_title：ACS medicinal chemistry letters

authors： Cee VJ,Chavez F Jr,Herberich B,Lanman BA,Pettus LH,Reed AB,Wu B,Wurz RP,Andrews KL,Chen J,Hickman D,Laszlo J 3rd,Lee MR,Guerrero N,Mattson BK,Nguyen Y,Mohr C,Rex K,Sastri CE,Wang P,Wu Q,Wu T,Xu Y,Zhou Y,Wi

更新日期：2016-02-12 00:00:00

abstract：:Structural modifications to the coumarin core and benzamide side chain of novobiocin have successfully transformed the natural product from a selective DNA gyrase inhibitor into a potent inhibitor of the Hsp90 C-terminus. However, no SAR studies have been conducted on the noviose appendage, which represents the rate-l...

journal_title：ACS medicinal chemistry letters

authors： Zhao H,Kusuma BR,Blagg BS

更新日期：2010-07-13 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：:A novel selective benzoxazepin inhibitor of PI3Kδ has been discovered. Beginning from compound 3, an αPI3K inhibitor, we utilized structure-based drug design and computational analysis of dihedral torsion angles to optimize for PI3Kδ isoform potency and isoform selectivity. Further medicinal chemistry optimization of ...

journal_title：ACS medicinal chemistry letters

authors： Safina BS,Elliott RL,Forrest AK,Heald RA,Murray JM,Nonomiya J,Pang J,Salphati L,Seward EM,Staben ST,Ultsch M,Wei B,Yang W,Sutherlin DP

更新日期：2017-08-25 00:00:00

abstract：:The influence of ionization states of hydroxamates and retrohydroxamates and the presence of zinc ions in the active site were investigated using the wild-type and E402Q mutant of MMP-9. The deprotonated hydroxamates showed a significantly enhanced enrichment factor in the presence of zinc ions. A pharmacophore model ...

journal_title：ACS medicinal chemistry letters

authors： Zhong H,Wees MA,Faure TD,Carrillo C,Arbiser J,Bowen JP

更新日期：2011-03-29 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：:We present the discovery and optimization of a novel series of inhibitors of bacterial UDP-N-acetylglucosamine 2-epimerase (called 2-epimerase in this paper). Starting from virtual screening hits, the activity of various inhibitory molecules was optimized using a combination of structure-based and rational design appr...

journal_title：ACS medicinal chemistry letters

authors： Xu Y,Brenning B,Clifford A,Vollmer D,Bearss J,Jones C,McCarthy V,Shi C,Wolfe B,Aavula B,Warner S,Bearss DJ,McCullar MV,Schuch R,Pelzek A,Bhaskaran SS,Stebbins CE,Goldberg AR,Fischetti VA,Vankayalapati H

更新日期：2013-12-12 00:00:00

abstract：:The renal outer medullary potassium channel (ROMK or Kir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a p...

journal_title：ACS medicinal chemistry letters

authors： Tang H,Walsh SP,Yan Y,de Jesus RK,Shahripour A,Teumelsan N,Zhu Y,Ha S,Owens KA,Thomas-Fowlkes BS,Felix JP,Liu J,Kohler M,Priest BT,Bailey T,Brochu R,Alonso-Galicia M,Kaczorowski GJ,Roy S,Yang L,Mills SG,Garcia M

更新日期：2012-03-28 00:00:00

abstract：:Several chemical probes have been developed for use in fluorescence polarization screening assays to aid in drug discovery for the bromodomain and extra-terminal domain (BET) proteins. However, few of those have been characterized in the literature. We have designed, synthesized, and thoroughly characterized a novel f...

journal_title：ACS medicinal chemistry letters

authors： Paulson CN,Guan X,Ayoub AM,Chan A,Karim RM,Pomerantz WCK,Schönbrunn E,Georg GI,Hawkinson JE

更新日期：2018-10-31 00:00:00

abstract：:Two rigid analogues of 5-ethylindolobenzazepinone 4, a potent cytotoxic agent and inhibitor of tubulin polymerization, were prepared. The first was the indane derivative 5, in which the ethyl group is attached to the benzo moiety. The second was the pyrrolidine analogue 6, in which the ethyl chain was bound to the lac...

journal_title：ACS medicinal chemistry letters

authors： Pons V,Beaumont S,Tran Huu Dau ME,Iorga BI,Dodd RH

更新日期：2011-06-05 00:00:00

abstract：:A new category of cationic meso-thiophenium porphyrins are introduced as possible alternatives to the popular meso-pyridinium porphyrins. Combinations of cationic porphyrins bearing meso-2-methylthiophenium and meso-4-hydroxyphenyl moieties T2(OH)2M (A2B2 type) and T(OH)3M (AB3 type) along with their zinc(II) complexe...

journal_title：ACS medicinal chemistry letters

authors： Mazumdar ZH,Sharma D,Mukherjee A,Basu S,Shukla PK,Jha T,Sengupta D

更新日期：2020-09-10 00:00:00

abstract：:A series of N-acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids (EMAC8000a-m) was designed and synthesized with the aim to target tumor associated carbonic anhydrase (hCA) isoforms IX and XII. Most of the compounds were selective inhibitors of the tumor associated hCA XII. Moreover, resolution of EMAC8000d racem...

journal_title：ACS medicinal chemistry letters

authors： Bianco G,Meleddu R,Distinto S,Cottiglia F,Gaspari M,Melis C,Corona A,Angius R,Angeli A,Taverna D,Alcaro S,Leitans J,Kazaks A,Tars K,Supuran CT,Maccioni E

更新日期：2017-06-21 00:00:00

abstract：:PAR2 antagonists have potential for treating inflammatory, respiratory, gastrointestinal, neurological, and metabolic disorders, but few antagonists are known. Derivatives of GB88 (3) suggest that all four of its components bind at distinct PAR2 sites with the isoxazole, cyclohexylalanine, and isoleucine determining a...

journal_title：ACS medicinal chemistry letters

authors： Yau MK,Liu L,Suen JY,Lim J,Lohman RJ,Jiang Y,Cotterell AJ,Barry GD,Mak JY,Vesey DA,Reid RC,Fairlie DP

更新日期：2016-10-10 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：:Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are membrane proteins encoded by four genes (HCN1-4) and widely distributed in the central and peripheral nervous system and in the heart. HCN channels are involved in several physiological functions, including the generation of rhythmic activity, and ...

journal_title：ACS medicinal chemistry letters

authors： Romanelli MN,Del Lungo M,Guandalini L,Zobeiri M,Gyökeres A,Árpádffy-Lovas T,Koncz I,Sartiani L,Bartolucci G,Dei S,Manetti D,Teodori E,Budde T,Cerbai E

更新日期：2019-02-06 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