Dipeptidyl Nitroalkenes as Potent Reversible Inhibitors of Cysteine Proteases Rhodesain and Cruzain.

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 have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (K i = 5.1 nM). We also present a model...

journal_title：ACS medicinal chemistry letters

authors： Chelliah MV,Eagen K,Guo Z,Chackalamannil S,Xia Y,Tsai H,Greenlee WJ,Ahn HS,Kurowski S,Boykow G,Hsieh Y,Chintala M

更新日期：2014-03-11 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 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for developme...

journal_title：ACS medicinal chemistry letters

authors： Sromek AW,Si YG,Zhang T,George SR,Seeman P,Neumeyer JL

更新日期：2011-03-10 00:00:00

abstract：:A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H3 receptor antagonists. The 4-(5-([1,4'-bipiperidin]-1'-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u was also evaluated i...

journal_title：ACS medicinal chemistry letters

authors： Rao AU,Shao N,Aslanian RG,Chan TY,Degrado SJ,Wang L,McKittrick B,Senior M,West RE Jr,Williams SM,Wu RL,Hwa J,Patel B,Zheng S,Sondey C,Palani A

更新日期：2011-11-21 00:00:00

abstract：:In this work, we present an investigation into the physical properties of a unique class of aromatic boronic acids, the benzoxaboroles. Using spectrophotometric methods, the ionization constants of a family of substituted benzoxaboroles are determined. Heterocyclic ring modifications are examined to determine their ef...

journal_title：ACS medicinal chemistry letters

authors： Tomsho JW,Pal A,Hall DG,Benkovic SJ

更新日期：2011-10-19 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：:In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular model...

journal_title：ACS medicinal chemistry letters

authors： Wu WL,Hao J,Domalski M,Burnett DA,Pissarnitski D,Zhao Z,Stamford A,Scapin G,Gao YD,Soriano A,Kelly TM,Yao Z,Powles MA,Chen S,Mei H,Hwa J

更新日期：2016-03-12 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：:Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with...

journal_title：ACS medicinal chemistry letters

authors： Feng Y,Park H,Bauer L,Ryu JC,Yoon SO

更新日期：2020-12-13 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：:A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in o...

journal_title：ACS medicinal chemistry letters

authors： Yue EW,Li YL,Douty B,He C,Mei S,Wayland B,Maduskuie T,Falahatpisheh N,Sparks RB,Polam P,Zhu W,Glenn J,Feng H,Zhang K,Li Y,He X,Katiyar K,Covington M,Feldman P,Shin N,Wang KH,Diamond S,Li Y,Koblish HK,Hall

更新日期：2019-10-17 00:00:00

abstract：:(+)- and (-)-Lesinurad were isolated as atropisomers from racemic lesinurad for the first time. No interconversion was observed between the two atropisomers under various conditions tested. The two atropisomers showed significant differences in hURAT1 highly expressed HEK293 cell-based inhibition assays, monkey pharma...

journal_title：ACS medicinal chemistry letters

authors： Wang J,Zeng W,Li S,Shen L,Gu Z,Zhang Y,Li J,Chen S,Jia X

更新日期：2017-02-14 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：:We report the discovery of benzoxaborole antitrypanosomal agents and their structure-activity relationships on central linkage groups and different substitution patterns in the sulfur-linked series. The compounds showed in vitro growth inhibition IC50 values as low as 0.02 μg/mL and in vivo efficacy in acute murine in...

journal_title：ACS medicinal chemistry letters

authors： Ding D,Zhao Y,Meng Q,Xie D,Nare B,Chen D,Bacchi CJ,Yarlett N,Zhang YK,Hernandez V,Xia Y,Freund Y,Abdulla M,Ang KH,Ratnam J,McKerrow JH,Jacobs RT,Zhou H,Plattner JJ

更新日期：2010-04-06 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：:In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4'-methoxy- and 4'-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these ...

journal_title：ACS medicinal chemistry letters

authors： Zheng Z,Groaz E,Snoeck R,De Jonghe S,Herdewijn P,Andrei G

更新日期：2020-12-09 00:00:00

abstract：:Small molecule inhibitors of the HIV-1 nucleocapsid protein (NC) are considered as promising agents in the treatment of HIV/AIDS. In an effort to exploit the privileged 2-amino-4-phenylthiazole moiety in NC inhibition, here we conceived, synthesized, and tested in vitro 18 NC inhibitors (NCIs) bearing a double functio...

journal_title：ACS medicinal chemistry letters

authors： Mori M,Dasso Lang MC,Saladini F,Palombi N,Kovalenko L,De Forni D,Poddesu B,Friggeri L,Giannini A,Malancona S,Summa V,Zazzi M,Mely Y,Botta M

更新日期：2018-12-07 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：: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：:A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust ph...

journal_title：ACS medicinal chemistry letters

authors： Walsh SP,Shahripour A,Tang H,Teumelsan N,Frie J,Zhu Y,Priest BT,Swensen AM,Liu J,Margulis M,Visconti R,Weinglass A,Felix JP,Brochu RM,Bailey T,Thomas-Fowlkes B,Alonso-Galicia M,Zhou X,Pai LY,Corona A,Hampton C,H

更新日期：2015-05-07 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：:The acyldepsipeptide (ADEP) antibiotics operate through a clinically unexploited mechanism of action and thus have attracted attention from several antibacterial development groups. The ADEP scaffold is synthetically tractable, and deep-seated modifications have produced extremely potent antibacterial leads against Gr...

journal_title：ACS medicinal chemistry letters

authors： Li Y,Lavey NP,Coker JA,Knobbe JE,Truong DC,Yu H,Lin YS,Nimmo SL,Duerfeldt AS

更新日期：2017-10-19 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：: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：: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：: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 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：:A new class of 4-aminoquinolines was synthesized and evaluated in vitro for antiplasmodial activity against both the chloroquine-sensitive (3D7) and -resistant (K1 and W2) strains. The most active compounds 3c-3e had acceptable cytotoxicity but showed strong inhibition toward a panel of cytochrome P450 enzymes in vitr...

journal_title：ACS medicinal chemistry letters

authors： Tukulula M,Njoroge M,Abay ET,Mugumbate GC,Wiesner L,Taylor D,Gibhard L,Norman J,Swart KJ,Gut J,Rosenthal PJ,Barteau S,Streckfuss J,Kameni-Tcheudji J,Chibale K

更新日期：2013-10-01 00:00:00

abstract：:Self-repair of nuclear DNA damage is the most known reason that leads to drug resistance of cancer tissue and limited therapeutic efficacy of anticancer drugs. Inhibition of protein phosphatase 2A (PP2A) would block DNA damage-induced defense of cancer cells to suppress DNA repair for enhanced cancer treatment. Here, ...

journal_title：ACS medicinal chemistry letters

authors： Cong Y,Wang L,Wang Z,He S,Zhou D,Jing X,Huang Y

更新日期：2016-08-24 00:00:00