Irreversible 4-Aminopiperidine Transglutaminase 2 Inhibitors for Huntington's Disease.

abstract：:Acetylcholinesterase is a critical enzyme that regulates neurotransmission by degrading the neurotransmitter acetylcholine in synapses of the nervous system. It is an important target for both therapeutic drugs that treat Alzheimer's disease and chemical warfare agents that cripple the nervous system and cause death t...

journal_title：ACS medicinal chemistry letters

authors： Cheung J,Gary EN,Shiomi K,Rosenberry TL

更新日期：2013-09-23 00:00:00

abstract：:A series of 1,4-disubstituted piperazine-based compounds were designed, synthesized, and evaluated as dopamine D2/D3 receptor ligands. The synthesis relies on the key multicomponent split-Ugi reaction, assessing its great potential in generating chemical diversity around the piperazine core. With the aim of evaluating...

journal_title：ACS medicinal chemistry letters

authors： Stucchi M,Gmeiner P,Huebner H,Rainoldi G,Sacchetti A,Silvani A,Lesma G

更新日期：2015-06-23 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 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：: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：:Acetaminophen (ApAP) is an electron donor capable of reducing radicals generated by redox cycling of hemeproteins. It acts on the prostaglandin H synthases (cyclooxygenases; COXs) to reduce the protoporphyrin radical cation in the peroxidase site of the enzyme, thus preventing the intra-molecular electron transfer tha...

journal_title：ACS medicinal chemistry letters

authors： Shchepin RV,Liu W,Yin H,Zagol-Ikapitte I,Amin T,Jeong BS,Roberts LJ 2nd,Oates JA,Porter NA,Boutaud O

更新日期：2013-08-08 00:00:00

abstract：:The effects of opioids in the central nervous system (CNS) provide significant benefit in the treatment of pain but can also lead to physical dependence and addiction, which has contributed to a growing opioid epidemic in the United States. Gastrointestinal dysfunction is an additional serious consequence of opioid us...

journal_title：ACS medicinal chemistry letters

authors： Long DD,Armstrong SR,Beattie DT,Campbell CB,Church TJ,Colson PJ,Dalziel SM,Jacobsen JR,Jiang L,Obedencio GP,Rapta M,Saito D,Stergiades I,Tsuruda PR,Van Dyke PM,Vickery RG

更新日期：2019-11-26 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：:Insulin-regulated aminopeptidase (IRAP) is a transmembrane zinc metallopeptidase with many important biological functions and an emerging pharmacological target. Although previous structural studies have given insight on how IRAP recognizes linear peptides, how it recognizes its physiological cyclic ligands remains el...

journal_title：ACS medicinal chemistry letters

authors： Mpakali A,Saridakis E,Giastas P,Maben Z,Stern LJ,Larhed M,Hallberg M,Stratikos E

更新日期：2020-06-02 00:00:00

abstract：:APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/P...

journal_title：ACS medicinal chemistry letters

authors： Buzard DJ,Kim SH,Lopez L,Kawasaki A,Zhu X,Moody J,Thoresen L,Calderon I,Ullman B,Han S,Lehmann J,Gharbaoui T,Sengupta D,Calvano L,Montalban AG,Ma YA,Sage C,Gao Y,Semple G,Edwards J,Barden J,Morgan M,Chen W,U

更新日期：2014-11-04 00:00:00

abstract：:Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of Plasmodium falciparum, the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, s...

journal_title：ACS medicinal chemistry letters

authors： Daub ME,Prudhomme J,Ben Mamoun C,Le Roch KG,Vanderwal CD

更新日期：2017-02-16 00:00:00

abstract：:Current treatment of toxoplasmosis targets the parasite's folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and h...

journal_title：ACS medicinal chemistry letters

authors： Welsch ME,Zhou J,Gao Y,Yan Y,Porter G,Agnihotri G,Li Y,Lu H,Chen Z,Thomas SB

更新日期：2016-09-17 00:00:00

abstract：:Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling and biological evaluation of 4,10-didesmethyl telithromycin (4), a novel desm...

journal_title：ACS medicinal chemistry letters

authors： Velvadapu V,Glassford I,Lee M,Paul T,Debrosse C,Klepacki D,Small MC,Mackerell AD Jr,Andrade RB

更新日期：2012-03-08 00:00:00

abstract：:Measuring innovation in the pharmaceutical industry is challenging. Counts of new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) are commonly used, but this measure only gauges quantity not innovativeness. A new indicator of innovation for small molecule and peptide drugs based on structu...

journal_title：ACS medicinal chemistry letters

authors： Wills TJ,Lipkus AH

更新日期：2020-09-10 00:00:00

abstract：:ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/...

journal_title：ACS medicinal chemistry letters

authors： Tang H,Zhu Y,Teumelsan N,Walsh SP,Shahripour A,Priest BT,Swensen AM,Felix JP,Brochu RM,Bailey T,Thomas-Fowlkes B,Pai LY,Hampton C,Corona A,Hernandez M,Metzger J,Forrest M,Zhou X,Owens K,Tong V,Parmee E,Roy S,K

更新日期：2016-05-12 00:00:00

abstract：:The signal transducer and activator of transcription 3 (STAT3) is considered to be an attractive therapeutic target for oncology drug development. We identified a N-[2-(1,3,4-oxadiazolyl)]-4-quinolinecarboxamide derivative, STX-0119, as a novel STAT3 dimerization inhibitor by a virtual screen using a customized versio...

journal_title：ACS medicinal chemistry letters

authors： Matsuno K,Masuda Y,Uehara Y,Sato H,Muroya A,Takahashi O,Yokotagawa T,Furuya T,Okawara T,Otsuka M,Ogo N,Ashizawa T,Oshita C,Tai S,Ishii H,Akiyama Y,Asai A

更新日期：2010-07-13 00:00:00

abstract：:Replication protein A (RPA) is the major human single stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and DNA-damage response (DDR). Inhibition of RPA-DNA interactions represents a therapeutic strategy for cancer drug discovery and has great potential to provide...

journal_title：ACS medicinal chemistry letters

authors： Gavande NS,VanderVere-Carozza PS,Pawelczak KS,Vernon TL,Jordan MR,Turchi JJ

更新日期：2020-01-02 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：:A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, includ...

journal_title：ACS medicinal chemistry letters

authors： Truax VM,Zhao H,Katzman BM,Prosser AR,Alcaraz AA,Saindane MT,Howard RB,Culver D,Arrendale RF,Gruddanti PR,Evers TJ,Natchus MG,Snyder JP,Liotta DC,Wilson LJ

更新日期：2013-09-05 00:00:00

abstract：:Two novel benzofuran derivatives coupled with (99m)Tc complexes were tested as probes for imaging cerebral β-amyloid plaques using single photon emission tomography. Although both derivatives bound to Aβ(1-42) aggregates, (99m)Tc-BAT-BF showed higher affinity than (99m)Tc-MAMA-BF. In sections of brain tissue from an a...

journal_title：ACS medicinal chemistry letters

authors： Ono M,Fuchi Y,Fuchigami T,Kobashi N,Kimura H,Haratake M,Saji H,Nakayama M

更新日期：2010-08-02 00:00:00

abstract：:Tuning the bioavailability of lidocaine was explored by its incorporation into the ionic liquid lidocainium docusate ([Lid][Doc]) and the deep eutectic Lidocaine·Ibuprofen (Lid·Ibu) and comparing the transdermal absorption of these with the crystalline salt lidocainium chloride ([Lid]Cl). Each form of lidocaine was di...

journal_title：ACS medicinal chemistry letters

authors： Berton P,Di Bona KR,Yancey D,Rizvi SAA,Gray M,Gurau G,Shamshina JL,Rasco JF,Rogers RD

更新日期：2017-04-12 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：:Collaborations between the pharmaceutical industry and contract research organizations continue to represent an attractive alternative to internal drug discovery within a single organization. This Viewpoint covers many of the business models and strategies that are employed in industry-contract research organization c...

journal_title：ACS medicinal chemistry letters

authors： Steadman VA

更新日期：2018-06-04 00:00:00

abstract：:The natural product L-783277 is a resorcylic lactone type covalent kinase inhibitor. We have prepared the 5'-deoxy analogue of L-783277 (1) in a stereoselective fashion. Remarkably, this analogue retains almost the full kinase inhibitory potential of natural L-783277, with low nanomolar IC50 values against the most se...

journal_title：ACS medicinal chemistry letters

authors： Liniger M,Neuhaus C,Hofmann T,Fransioli-Ignazio L,Jordi M,Drueckes P,Trappe J,Fabbro D,Altmann KH

更新日期：2010-10-20 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：: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：:Human mitogen-activated protein kinases (MAPK)-interacting kinases 1 and 2 (Mnk1/2) are promising anticancer targets. Mnks possess special insertions and a DFD-motif that are distinct from other kinases. Crystallographic studies of Mnk1/2 have revealed that the DFD-motif adopts the DFG/D-out conformation in which resi...

journal_title：ACS medicinal chemistry letters

authors： Hou J,Teo T,Sykes MJ,Wang S

更新日期：2013-06-24 00:00:00

abstract：:An active site mapping of human cathepsin B with dipeptide nitrile inhibitors was performed for a combinatorial approach by introducing several points of diversity and stepwise optimizing the inhibitor structure. To address the occluding loop of cathepsin B by a carboxylate moiety, click chemistry to generate linker-c...

journal_title：ACS medicinal chemistry letters

authors： Schmitz J,Li T,Bartz U,Gütschow M

更新日期：2015-12-28 00:00:00

abstract：:A novel two-step in situ method for targeted antitumor drug release by supramolecular assembly (Fc-CPT@HACD) was constructed using camptothecin prodrug (Fc-CPT) and β-cyclodextrin (β-CD)-modified hyaluronic acid (HACD). Benefiting from the overexpressed H2O2 and glutathione (GSH) in tumor cells, Fc-CPT@HACD can be dis...

journal_title：ACS medicinal chemistry letters

authors： Fu HG,Chen Y,Yu Q,Liu Y

更新日期：2020-05-18 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