Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor.

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：:GPBAR1 agonists have been identified as potential leads for the treatment of diseases related to colon inflammation such as Crohn's and ulcerative colitis. In this paper, we report the discovery of a small library of hyodeoxycholane analogues, decorated at C-6 with different substituents, as potent and selective GPBAR...

journal_title：ACS medicinal chemistry letters

authors： Marino S,Finamore C,Biagioli M,Carino A,Marchianò S,Roselli R,Giorgio CD,Bordoni M,Di Leva FS,Novellino E,Cassiano C,Limongelli V,Zampella A,Festa C,Fiorucci S

更新日期：2020-03-02 00:00:00

abstract：:The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chemistry (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series containing 2-substitute...

journal_title：ACS medicinal chemistry letters

authors： Liu J,Yu Y,Kelly J,Sha D,Alhassan AB,Yu W,Maletic MM,Duffy JL,Klein DJ,Holloway MK,Carroll S,Howell BJ,Barnard RJO,Wolkenberg S,Kozlowski JA

更新日期：2020-10-13 00:00:00

abstract：:Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood-brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules...

journal_title：ACS medicinal chemistry letters

authors： Heffron TP,Ndubaku CO,Salphati L,Alicke B,Cheong J,Drobnick J,Edgar K,Gould SE,Lee LB,Lesnick JD,Lewis C,Nonomiya J,Pang J,Plise EG,Sideris S,Wallin J,Wang L,Zhang X,Olivero AG

更新日期：2016-02-16 00:00:00

abstract：:Natural and synthetic histone deacetylase (HDAC) inhibitors generally derive their strong binding affinity and high potency from a key functional group that binds to the Zn(2+) ion within the enzyme active site. However, this feature is also thought to carry the potential liability of undesirable off-target interactio...

journal_title：ACS medicinal chemistry letters

authors： Vickers CJ,Olsen CA,Leman LJ,Ghadiri MR

更新日期：2012-04-26 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：: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 high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key str...

journal_title：ACS medicinal chemistry letters

authors： Dubernet M,Duguet N,Colliandre L,Berini C,Helleboid S,Bourotte M,Daillet M,Maingot L,Daix S,Delhomel JF,Morin-Allory L,Routier S,Walczak R

更新日期：2013-04-10 00:00:00

abstract：:Myeloperoxidase (MPO) is a key antimicrobial enzyme, playing a normal role in host defense, but also contributing to inflammatory conditions including neuroinflammatory diseases such as Parkinson's and Alzheimer's. We synthesized and characterized more than 50 quinazolin-4(1H)-one derivatives and showed that this clas...

journal_title：ACS medicinal chemistry letters

authors： Li Y,Ganesh T,Diebold BA,Zhu Y,McCoy JW,Smith SM,Sun A,Lambeth JD

更新日期：2015-08-31 00:00:00

abstract：:[This corrects the article DOI: 10.1021/acsmedchemlett.9b00612.]. ...

journal_title：ACS medicinal chemistry letters

authors： Kaiser TM,Dentmon ZW,Dalloul CE,Sharma SK,Liotta DC

更新日期：2020-06-24 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：:The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are p...

journal_title：ACS medicinal chemistry letters

authors： Liu G,Gaines JC,Robbins KJ,Lazo ND

更新日期：2012-08-28 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：:IκB kinase β (IKKβ or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and p...

journal_title：ACS medicinal chemistry letters

authors： Kerns JK,Busch-Petersen J,Fu W,Boehm JC,Nie H,Muratore M,Bullion A,Lin G,Li H,Davis R,Lin X,Lakdawala AS,Cousins R,Field R,Payne J,Miller DD,Bamborough P,Christopher JA,Baldwin I,Osborn RR,Yonchuk J,Webb E,Rum

更新日期：2018-10-30 00:00:00

abstract：:Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation...

journal_title：ACS medicinal chemistry letters

authors： Pettersson M,Johnson DS,Humphrey JM,Butler TW,Am Ende CW,Fish BA,Green ME,Kauffman GW,Mullins PB,O'Donnell CJ,Stepan AF,Stiff CM,Subramanyam C,Tran TP,Vetelino BC,Yang E,Xie L,Bales KR,Pustilnik LR,Steyn SJ,Wood K

更新日期：2015-04-03 00:00:00

abstract：:GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic β-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclizati...

journal_title：ACS medicinal chemistry letters

authors： Negoro N,Sasaki S,Mikami S,Ito M,Suzuki M,Tsujihata Y,Ito R,Harada A,Takeuchi K,Suzuki N,Miyazaki J,Santou T,Odani T,Kanzaki N,Funami M,Tanaka T,Kogame A,Matsunaga S,Yasuma T,Momose Y

更新日期：2010-06-18 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：:Purine-rich foods have long been suspected as a major cause of hyperuricemia. We hypothesized that inhibition of human concentrative nucleoside transporter 2 (hCNT2) would suppress increases in serum urate levels derived from dietary purines. To test this hypothesis, the development of potent hCNT2 inhibitors was requ...

journal_title：ACS medicinal chemistry letters

authors： Tatani K,Hiratochi M,Nonaka Y,Isaji M,Shuto S

更新日期：2015-01-28 00:00:00

abstract：:The attachment of lipids to C- or N-terminally positioned lysine side-chain amino groups increases the activity of a short synthetic (Arg-Trp)3 antimicrobial peptide significantly, making these peptides even active against pathogenic Gram-negative bacteria. Thus, a peptide with strong activity against S. aureus (1.1-2...

journal_title：ACS medicinal chemistry letters

authors： Albada HB,Prochnow P,Bobersky S,Langklotz S,Schriek P,Bandow JE,Metzler-Nolte N

更新日期：2012-09-04 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：:Reactive oxygen species, contributing to oxidant-antioxidant imbalance, initiate damage to the airways cells, inflammatory processes, and further pathophysiological effects. Enhancing antioxidant properties is the main prophylactic and therapeutic challenge. In this work, a newly synthesized and biocompatible structur...

journal_title：ACS medicinal chemistry letters

authors： Wiśniewski M,Bieniek A,Roszek K,Czarnecka J,Bolibok P,Ferrer P,da Silva I,Terzyk AP

更新日期：2018-11-19 00:00:00

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 novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure-activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carbo...

journal_title：ACS medicinal chemistry letters

authors： Pan S,Gray NS,Gao W,Mi Y,Fan Y,Wang X,Tuntland T,Che J,Lefebvre S,Chen Y,Chu A,Hinterding K,Gardin A,End P,Heining P,Bruns C,Cooke NG,Nuesslein-Hildesheim B

更新日期：2013-01-04 00:00:00

abstract：:Highly toxic bacterial ionophores are commonly used in veterinary medicine, but their therapeutic index is too narrow for human usage. With the goal of developing ionophores with a broader therapeutic index, we constructed highly derivatized synthetic ionophores. The toxicities of crown ether host-rotaxanes (CEHR's) a...

journal_title：ACS medicinal chemistry letters

authors： Smithrud DB,Wang X,Tarapore P,Ho SM

更新日期：2013-01-10 00:00:00

abstract：:CREB (cAMP response element binding protein) has been shown to play an important role in tumor initiation, progression, and metastasis. We discovered that naphthol AS-E, a cell-permeable CREB inhibitor, presented antiproliferative activity in a broad panel of cancer cell lines in vitro. However, it has limited aqueous...

journal_title：ACS medicinal chemistry letters

authors： Li BX,Xie F,Fan Q,Barnhart KM,Moore CE,Rheingold AL,Xiao X

更新日期：2014-08-22 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：: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：: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：: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：:We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bio...

journal_title：ACS medicinal chemistry letters

authors： Yang MG,Xiao Z,Cherney RJ,Tebben AJ,Batt DG,Brown GD,Chen J,Cvijic ME,Dabros M,Duncia JV,Galella M,Gardner DS,Khandelwal P,Ko SS,Malley MF,Mo R,Pang J,Rose AV,Santella JB 3rd,Shi H,Srivastava A,Traeger SC,Wang

更新日期：2019-01-16 00:00:00