B-973, a Novel α7 nAChR Ago-PAM: Racemic and Asymmetric Synthesis, Electrophysiological Studies, and in Vivo Evaluation.

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：:Despite several years of research, only a handful of β-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. ...

journal_title：ACS medicinal chemistry letters

authors： Oehlrich D,Peschiulli A,Tresadern G,Van Gool M,Vega JA,De Lucas AI,Alonso de Diego SA,Prokopcova H,Austin N,Van Brandt S,Surkyn M,De Cleyn M,Vos A,Rombouts FJR,Macdonald G,Moechars D,Gijsen HJM,Trabanco AA

更新日期：2019-07-02 00:00:00

abstract：:Novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19-34 have been synthesized and appraised for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route at doses ranging from 96 mg/kg × 4 days to 24 mg/kg × 4 days. The most active compound...

journal_title：ACS medicinal chemistry letters

authors： Maurya R,Soni A,Anand D,Ravi M,Raju KS,Taneja I,Naikade NK,Puri SK,Wahajuddin,Kanojiya S,Yadav PP

更新日期：2012-12-11 00:00:00

abstract：:Glucocorticoids are one of the most utilized and effective therapies in treating T-cell acute lymphoblastic leukemia. However, patients often develop resistance to glucocorticoids, rendering these therapies ineffective. We screened 9517 compounds, selected for their lead-like properties, chosen from among 3 372 615 co...

journal_title：ACS medicinal chemistry letters

authors： Cantley AM,Welsch M,Ambesi-Impiombato A,Sanchez-Martin M,Kim MY,Bauer A,Ferrando A,Stockwell BR

更新日期：2014-04-25 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：:Antibiotic-resistant bacteria are emerging at an alarming rate in both hospital and community settings. Motivated by this issue, we have prepared desmethyl (i.e., replacing methyl groups with hydrogens) analogues of third-generation macrolide drugs telithromycin (TEL, 2) and cethromycin (CET, 6), both of which are sem...

journal_title：ACS medicinal chemistry letters

authors： Wagh B,Paul T,Debrosse C,Klepacki D,Small MC,Mackerell AD Jr,Andrade RB

更新日期：2013-11-14 00:00:00

abstract：:A series of 12N-substituted sophoridinamine derivatives were synthesized and evaluated for their cytotoxic activities in human HepG2 hepatoma cells. Structure-activity relationship revealed that introduction of a suitable arylidene or arylethyl at the N'-end could greatly enhance antiproliferation potency. Among them,...

journal_title：ACS medicinal chemistry letters

authors： Bi C,Zhang N,Yang P,Ye C,Wang Y,Fan T,Shao R,Deng H,Song D

更新日期：2017-01-05 00:00:00

abstract：:γ-Aminobutyric acid type A (GABAA) receptors are key mediators of central inhibitory neurotransmission and have been implicated in several disorders of the central nervous system. Some positive allosteric modulators (PAMs) of this receptor provide great therapeutic benefits to patients. However, adverse effects remain...

journal_title：ACS medicinal chemistry letters

authors： Blom AEM,Su JY,Repka LM,Reisman SE,Dougherty DA

更新日期：2020-09-15 00:00:00

abstract：:By employing a phenotypic screen, a set of compounds, exemplified by 1, were identified which potentiate the ability of histone deacetylase inhibitor vorinostat to reverse HIV latency. Proteome enrichment followed by quantitative mass spectrometric analysis employing a modified analogue of 1 as affinity bait identifie...

journal_title：ACS medicinal chemistry letters

authors： Bukhtiyarova M,Cook EM,Hancock PJ,Hruza AW,Shaw AW,Adam GC,Barnard RJO,McKenna PM,Holloway MK,Bell IM,Carroll S,Cornella-Taracido I,Cox CD,Kutchukian PS,Powell DA,Strickland C,Trotter BW,Tudor M,Wolkenberg S,Li J,

更新日期：2020-12-23 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 phenethylamine backbone is a privileged substructure found in a wide variety of G protein-coupled receptor (GPCR) ligands. This includes both endogenous neurotransmitters and active pharmaceutical agents. More than 20 structurally unique heterocyclic phenethylamine derivatives were broadly evaluated for GPCR affin...

journal_title：ACS medicinal chemistry letters

authors： Porter MR,Xiao H,Wang J,Smith SB,Topczewski JJ

更新日期：2019-09-23 00:00:00

abstract：:Representative d-amino acid oxidase (DAAO) inhibitors were subjected to in vitro liver microsomal stability tests in the absence or presence of uridine diphosphate glucuronic acid (UDPGA). While carboxylate-based DAAO inhibitors displayed little glucuronidation, most DAAO inhibitors containing α-hydroxycarbonyl moiety...

journal_title：ACS medicinal chemistry letters

authors： Zimmermann SC,Rais R,Alt J,Burzynski C,Slusher BS,Tsukamoto T

更新日期：2014-10-21 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：: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：:ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health, these protein transporters have been implicated in the emerging resistance of cancer cells to a variety of structurally and functionally diverse antic...

journal_title：ACS medicinal chemistry letters

authors： Peña-Solórzano D,Scholler M,Bernhardt G,Buschauer A,König B,Ochoa-Puentes C

更新日期：2018-07-25 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：:Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA4 hydrolase (LTA4H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure-a...

journal_title：ACS medicinal chemistry letters

authors： Hiesinger K,Schott A,Kramer JS,Blöcher R,Witt F,Wittmann SK,Steinhilber D,Pogoryelov D,Gerstmeier J,Werz O,Proschak E

更新日期：2019-10-30 00:00:00

abstract：:A focused high throughput screening for GPR139 was completed for a select 100K compounds, and new agonist leads were identified. Subsequent analysis and structure-activity relationship studies identified (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide 7c as a potent and selective agonist of hGPR139 with ...

journal_title：ACS medicinal chemistry letters

authors： Dvorak CA,Coate H,Nepomuceno D,Wennerholm M,Kuei C,Lord B,Woody D,Bonaventure P,Liu C,Lovenberg T,Carruthers NI

更新日期：2015-07-20 00:00:00

abstract：:Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of ...

journal_title：ACS medicinal chemistry letters

authors： Szokol B,Gyulavári P,Kurkó I,Baska F,Szántai-Kis C,Greff Z,Orfi Z,Peták I,Pénzes K,Torka R,Ullrich A,Orfi L,Vántus T,Kéri G

更新日期：2014-01-30 00:00:00

abstract：:A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibit...

journal_title：ACS medicinal chemistry letters

authors： Hirata K,Kotoku M,Seki N,Maeba T,Maeda K,Hirashima S,Sakai T,Obika S,Hori A,Hase Y,Yamaguchi T,Katsuda Y,Hata T,Miyagawa N,Arita K,Nomura Y,Asahina K,Aratsu Y,Kamada M,Adachi T,Noguchi M,Doi S,Crowe P,Bradle

更新日期：2015-11-04 00:00:00

abstract：:The racemic product of the Betti reaction of 5-chloro-8-hydroxyquinoline, benzaldehyde and 2-aminopyridine was separated by chiral HPLC to determine which enantiomer inhibited botulinum neurotoxin serotype A. When the enantiomers unexpectedly proved to have comparable activity, the absolute structures of (+)-(R)-1 and...

journal_title：ACS medicinal chemistry letters

authors： Cardellina JH 2nd,Vieira RC,Eccard V,Skerry J,Montgomery V,Campbell Y,Roxas-Duncan V,Leister W,Leclair CA,Maloney DJ,Padula D,Pescitelli G,Khavrutskii I,Hu X,Wallqvist A,Smith LA

更新日期：2011-03-10 00:00:00

abstract：:We have developed a novel albumin-binding prodrug of doxorubicin that incorporates p-aminobenzyloxycarbonyl (PABC) as a 1,6 self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, as a substrate for the prostate-specific antigen (PSA) that is overexpressed in prostate carcinoma and represe...

journal_title：ACS medicinal chemistry letters

authors： Elsadek B,Graeser R,Warnecke A,Unger C,Saleem T,El-Melegy N,Madkor H,Kratz F

更新日期：2010-05-26 00:00:00

abstract：:Two series of novel LOXL2 enzyme inhibitors are described: benzylamines substituted with electron withdrawing groups at the para-position and 2-substituted pyridine-4-ylmethanamines. The most potent compound, (2-chloropyridin-4-yl)methanamine 20 (hLOXL2 IC50 = 126 nM), was shown to be selective for LOXL2 over LOX and ...

journal_title：ACS medicinal chemistry letters

authors： Hutchinson JH,Rowbottom MW,Lonergan D,Darlington J,Prodanovich P,King CD,Evans JF,Bain G

更新日期：2017-03-01 00:00:00

abstract：:Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral ...

journal_title：ACS medicinal chemistry letters

authors： Bungard CJ,Williams PD,Schulz J,Wiscount CM,Holloway MK,Loughran HM,Manikowski JJ,Su HP,Bennett DJ,Chang L,Chu XJ,Crespo A,Dwyer MP,Keertikar K,Morriello GJ,Stamford AW,Waddell ST,Zhong B,Hu B,Ji T,Diamond TL,Ba

更新日期：2017-11-13 00:00:00

abstract：:The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cel...

journal_title：ACS medicinal chemistry letters

authors： Yu T,Li N,Wu C,Guan A,Li Y,Peng Z,He M,Li J,Gong Z,Huang L,Gao B,Hao D,Sun J,Pan Y,Shen L,Chan C,Lu X,Yuan H,Li Y,Li J,Chen S

更新日期：2018-02-27 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：:Derivatization efforts were continued to discover backups for a potent selective PPARγ modulator, DS-6930. In this Letter, the replacement of 2-pyridine ring in DS-6930 with 3- or 4-pyridyl group is reported. As the introduction of substituents on the pyridine ring did not provide potent partial agonists, modification...

journal_title：ACS medicinal chemistry letters

authors： Shinozuka T,Tsukada T,Fujii K,Tokumaru E,Matsui Y,Wakimoto S,Ogata T,Araki K,Sawamura R,Watanabe N,Mori M,Tanaka J

更新日期：2019-02-26 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：:[This corrects the article DOI: 10.1021/acsmedchemlett.8b00507.]. ...

journal_title：ACS medicinal chemistry letters

authors： De Simone A,La Pietra V,Betari N,Petragnani N,Conte M,Daniele S,Pietrobono D,Martini C,Petralla S,Casadei R,Davani L,Frabetti F,Russomanno P,Novellino E,Montanari S,Tumiatti V,Ballerini P,Sarno F,Nebbioso A,Altucci

更新日期：2019-08-06 00:00:00

abstract：:A focused multiply N-methylated library of a cyclic hexapeptidic somatostatin analogue: MK678 cyclo(-MeAYwKVF-) was generated, which resulted in the unexpected observation of an efficacious tetra-N-methylated analogue, cyclo(-MeAYMewMeKVMeF-) with a potent inhibitory action on sensory neuropeptide release in vitro and...

journal_title：ACS medicinal chemistry letters

authors： Chatterjee J,Laufer B,Beck JG,Helyes Z,Pintér E,Szolcsányi J,Horvath A,Mandl J,Reubi JC,Kéri G,Kessler H

更新日期：2011-04-04 00:00:00