Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor.

abstract：:Modifications at the basic nitrogen of the benzomorphan scaffold allowed the development of compounds able to segregate physiological responses downstream of the receptor signaling, opening new possibilities in opioid drug development. Alkylation of the phenyl ring in the N-substituent of the MOR-agonist/DOR-antagonis...

journal_title：ACS medicinal chemistry letters

authors： Pasquinucci L,Parenti C,Ruiz-Cantero MC,Georgoussi Z,Pallaki P,Cobos EJ,Amata E,Marrazzo A,Prezzavento O,Arena E,Dichiara M,Salerno L,Turnaturi R

更新日期：2020-01-28 00:00:00

abstract：:Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in mo...

journal_title：ACS medicinal chemistry letters

authors： Bell IM,Gallicchio SN,Wood MR,Quigley AG,Stump CA,Zartman CB,Fay JF,Li CC,Lynch JJ,Moore EL,Mosser SD,Prueksaritanont T,Regan CP,Roller S,Salvatore CA,Kane SA,Vacca JP,Selnick HG

更新日期：2010-01-12 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：:Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for the folding and maturation of client proteins that are associated with all ten hallmarks of cancer. Hsp90 N-terminal pan inhibitors have experienced unfavorable results in clinical trials due to induction of the heat shock response (HSR), a...

journal_title：ACS medicinal chemistry letters

authors： Pugh KW,Zhang Z,Wang J,Xu X,Munthali V,Zuo A,Blagg BSJ

更新日期：2020-06-11 00:00:00

abstract：:Pyxinol, the main metabolite of 20S-protopanaxadiol in human liver, was chosen as a novel skeleton for the development of anti-inflammatory agents. Pyxinol derivatives modified at C-3, C-12, or C-25 and selected stereoisomers were designed, prepared, and investigated for in vitro anti-inflammatory activities. Structur...

journal_title：ACS medicinal chemistry letters

authors： Sun Y,Fang X,Gao M,Wang C,Gao H,Bi W,Tang H,Cui Y,Zhang L,Fan H,Yu H,Yang G

更新日期：2020-02-12 00:00:00

abstract：:Visible light-mediated photocatalysis, which relies on the ability of photocatalysts to absorb low-energy visible light and engage in single-electron transfer (SET) or energy transfer (ET) processes with organic substrates, has emerged as one of the fastest growing fields in organic synthesis. This catalytic platform ...

journal_title：ACS medicinal chemistry letters

authors： Li P,Terrett JA,Zbieg JR

更新日期：2020-09-21 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：: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：: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：:Approximately 1.7 million Americans develop hospital associated infections each year, resulting in more than 98,000 deaths. One of the main contributors to such infections is the Gram-negative pathogen Acinetobacter baumannii. Recently, it was reported that aryl 2-aminoimidazole (2-AI) compounds potentiate macrolide a...

journal_title：ACS medicinal chemistry letters

authors： Hubble VB,Bartholomew KR,Weig AW,Brackett SM,Barlock SL,Mattingly AE,Nemeth AM,Melander RJ,Melander C

更新日期：2020-08-12 00:00:00

abstract：:An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared to the corresponding 4-phenylpiperazine analogue. To explore a possible rein...

journal_title：ACS medicinal chemistry letters

authors： Liégeois JF,Lespagnard M,Meneses Salas E,Mangin F,Scuvée-Moreau J,Dilly S

更新日期：2014-01-29 00:00:00

abstract：:We recently reported a series of 2,6-dipeptidyl-anthraquinone conjugates (AQs) as Trans-Activation Response element (TAR) RNA-binding agents able to inhibit in vitro the HIV-1 nucleocapsid (NC) protein-mediated processes. Because NC is a highly adaptable nucleic acid chaperone assisting several crucial steps along rev...

journal_title：ACS medicinal chemistry letters

authors： Gamba E,Sosic A,Saccone I,Magli E,Frecentese F,Gatto B

更新日期：2020-03-23 00:00:00

abstract：:EPAC proteins are therapeutic targets for the potential treatment of cardiac hypertrophy and cancer metastasis. Several laboratories use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1 in various disease states. Here, we report SAR studies with tetrahydroquinoline analogs that explore various functio...

journal_title：ACS medicinal chemistry letters

authors： Sonawane YA,Zhu Y,Garrison JC,Ezell EL,Zahid M,Cheng X,Natarajan A

更新日期：2017-10-02 00:00:00

abstract：:P-glycoprotein (Pgp) is capable of recognizing and transporting a wide range of chemically diverse compounds in vivo. Overcoming Pgp-mediated efflux can represent a significant challenge when penetration into the central nervous system is required or within the context of developing anticancer therapies. While numerou...

journal_title：ACS medicinal chemistry letters

authors： Gunaydin H,Weiss MM,Sun Y

更新日期：2012-11-06 00:00:00

abstract：:Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite P. yoelii (Py) as well as hypnozoites of the simian parasite P. cynomolgi (Pc). We applied these various assays to the cell-based lea...

journal_title：ACS medicinal chemistry letters

authors： Zou B,Nagle A,Chatterjee AK,Leong SY,Tan LJ,Sim WL,Mishra P,Guntapalli P,Tully DC,Lakshminarayana SB,Lim CS,Tan YC,Abas SN,Bodenreider C,Kuhen KL,Gagaring K,Borboa R,Chang J,Li C,Hollenbeck T,Tuntland T,Zeeman A

更新日期：2014-07-06 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 series of structurally diverse azaspirodecanone and spirooxazolidinone analogues were designed and synthesized as potent and selective somatostatin receptor subtype 5 (SSTR5) antagonists. Four optimized compounds each representing a subseries showed improvement in their metabolic stability and pharmacokinetic profil...

journal_title：ACS medicinal chemistry letters

authors： Liu W,Hussain Z,Zang Y,Sweis RF,Romero FA,Finke PE,Moningka R,Bao J,Plotkin MA,Shang J,Dingley KH,Salituro G,Murphy BA,Howard AD,Ujjainwalla F,Wood HB,Duffy JL

更新日期：2018-10-05 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：:A series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and in vitro DMPK profiles are discussed. Good in vivo exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed signific...

journal_title：ACS medicinal chemistry letters

authors： Pryde DC,Marron BE,West CW,Reister S,Amato G,Yoger K,Antonio B,Padilla K,Cox PJ,Turner J,Warmus JS,Swain NA,Omoto K,Mahoney JH,Gerlach AC

更新日期：2017-05-18 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：:Based on the potent Kv7 agonist RL-81, we prepared new lead structures with greatly improved selectivity for Kv7.2/Kv7.3 over related potassium channels, i.e., Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5. RL-36 and RL-12 maintain an agonist EC2x of ca. 1 μM on Kv7.2/Kv7.3 in a high-throughput assay on an automated electrophysio...

journal_title：ACS medicinal chemistry letters

authors： Liu R,Tzounopoulos T,Wipf P

更新日期：2019-05-08 00:00:00

abstract：:The solution behavior of auranofin, Et3PAuCl  and Et3PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward re...

journal_title：ACS medicinal chemistry letters

authors： Marzo T,Cirri D,Gabbiani C,Gamberi T,Magherini F,Pratesi A,Guerri A,Biver T,Binacchi F,Stefanini M,Arcangeli A,Messori L

更新日期：2017-09-06 00:00:00

abstract：:This study was aimed at investigating the antitumor activity of novel 2-oxindole derivatives against a well-characterized human nonsmall cell lung cancer (NSCLC) cell line. Test compounds produced an antiproliferative activity in the low micromolar/submicromolar range of concentrations and significantly induced typica...

journal_title：ACS medicinal chemistry letters

authors： Nesi G,Sestito S,Mey V,Ricciardi S,Falasca M,Danesi R,Lapucci A,Breschi MC,Fogli S,Rapposelli S

更新日期：2013-10-18 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：: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：: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：: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 new pseudopeptide epoxide inhibitor, designed for irreversible binding to HIV protease (HIV-PR), has been synthesized and characterized in solution and in the solid state. However, the crystal structure of the complex obtained by inhibitor-enzyme cocrystallization revealed that a minor isomer, with inverted configur...

journal_title：ACS medicinal chemistry letters

authors： Benedetti F,Berti F,Campaner P,Fanfoni L,Demitri N,Olajuyigbe FM,De March M,Geremia S

更新日期：2014-07-14 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：:Primary open angle glaucoma is the second most common cause of blindness worldwide. Nitric oxide has recently received particular attention as a potential antiglaucoma agent. In this work, gem-dinitroalkyl benzenes are evaluated for their capability to act as a new class of IOP lowering agents. These derivatives have ...

journal_title：ACS medicinal chemistry letters

authors： Blangetti M,Rolando B,Marini E,Chegaev K,Guglielmo S,Lazzarato L,Lucarini L,Masini E,Fruttero R

更新日期：2017-09-13 00:00:00