Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction.

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：: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：: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：: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：: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

abstract：:A novel modulator of sodium ion currents was synthesized in 6 steps from a protected dihydroxypyrrolidine nitrone, via 1,3-dipolar cycloaddition reaction with acrylamide. Sodium ion currents in B50 cells were evaluated in comparison to saxitoxin and tetrodotoxin, and revealed an IC(50) of 15.7 muM. The new compound sh...

journal_title：ACS medicinal chemistry letters

authors： Mao H,Fieber LA,Gawley RE

更新日期：2010-03-31 00:00:00

abstract：:This research explores the first design and synthesis of macrocyclic peptide aldehydes as potent inhibitors of the 20S proteasome. Two novel macrocyclic peptide aldehydes based on the ring-size of the macrocyclic natural product TMC-95 were prepared and evaluated as inhibitors of the 20S proteasome. Both compounds inh...

journal_title：ACS medicinal chemistry letters

authors： Wilson DL,Meininger I,Strater Z,Steiner S,Tomlin F,Wu J,Jamali H,Krappmann D,Götz MG

更新日期：2016-01-15 00:00:00

abstract：:With the COVID-19 pandemic, the evolutionary fate of SARS-CoV-2 becomes a matter of utmost concern. Mutation D614G in the spike (S) protein has become dominant, and recent evidence suggests it yields a more stable phenotype with higher transmission efficacy. We carry out a structural analysis that provides mechanistic...

journal_title：ACS medicinal chemistry letters

authors： Fernández A

更新日期：2020-08-17 00:00:00

abstract：:We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in v...

journal_title：ACS medicinal chemistry letters

authors： Xue CB,Wang A,Han Q,Zhang Y,Cao G,Feng H,Huang T,Zheng C,Xia M,Zhang K,Kong L,Glenn J,Anand R,Meloni D,Robinson DJ,Shao L,Storace L,Li M,Hughes RO,Devraj R,Morton PA,Rogier DJ,Covington M,Scherle P,Diamond

更新日期：2011-10-05 00:00:00

abstract：:Using a multiplexed, reporter gene-based, high-throughput screen, we identified 9-fluoro-7-hydroxy-3-methyl-5-oxo-N-(pyridin-3-ylmethyl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxamide as a TLR2 agonist. Preliminary structure-activity relationship studies on the carboxamide moiety led to the identification o...

journal_title：ACS medicinal chemistry letters

authors： Hu Z,Banothu J,Beesu M,Gustafson CJ,Brush MJH,Trautman KL,Salyer ACD,Pathakumari B,David SA

更新日期：2018-12-20 00:00:00

abstract：:We report a series of lipidated α-AApeptides that mimic the structure and function of natural antimicrobial lipopeptides. Several short lipidated α-AApeptides show broad-spectrum activity against a range of clinically related Gram-positive and Gram-negative bacteria as well as fungus. Their antimicrobial activity and ...

journal_title：ACS medicinal chemistry letters

authors： Hu Y,Amin MN,Padhee S,Wang RE,Qiao Q,Bai G,Li Y,Mathew A,Cao C,Cai J

更新日期：2012-07-12 00:00:00

abstract：:A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overc...

journal_title：ACS medicinal chemistry letters

authors： Huang X,Brubaker J,Zhou W,Biju PJ,Xiao L,Shao N,Huang Y,Dong L,Liu Z,Bitar R,Buevich A,Jung J,Peterson SL,Butcher JW,Close J,Martinez M,MacCoss RN,Zhang H,Crawford S,McCormick KD,Aslanian R,Nargund R,Correll C

更新日期：2018-06-23 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：:Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and b...

journal_title：ACS medicinal chemistry letters

authors： Glassford I,Lee M,Wagh B,Velvadapu V,Paul T,Sandelin G,DeBrosse C,Klepacki D,Small MC,MacKerell AD Jr,Andrade RB

更新日期：2014-07-16 00:00:00

abstract：:Although heparan sulfate (HS) has been implicated in facilitating entry of enveloped viruses including herpes simplex virus (HSV), small molecules that effectively compete with this abundant, cell surface macromolecule remain unknown. We reasoned that entry of HSV-1 involving its glycoprotein D (gD) binding to HS coul...

journal_title：ACS medicinal chemistry letters

authors： Gangji RN,Sankaranarayanan NV,Elste J,Al-Horani RA,Afosah DK,Joshi R,Tiwari V,Desai UR

更新日期：2018-07-16 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

abstract：:A series of oxyguanidine analogues of the cysteine protease inhibitor WRR-483 were synthesized and evaluated against cruzain, the major cysteine protease of the protozoan parasite Trypanosoma cruzi. Kinetic analyses of these analogues indicated that they have comparable potency to previously prepared vinyl sulfone cru...

journal_title：ACS medicinal chemistry letters

authors： Jones BD,Tochowicz A,Tang Y,Cameron MD,McCall LI,Hirata K,Siqueira-Neto JL,Reed SL,McKerrow JH,Roush WR

更新日期：2015-12-15 00:00:00

abstract：:A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interact...

journal_title：ACS medicinal chemistry letters

authors： Millan DS,Kayser-Bricker KJ,Martin MW,Talbot AC,Schiller SER,Herbertz T,Williams GL,Luke GP,Hubbs S,Alvarez Morales MA,Cardillo D,Troccolo P,Mendes RL,McKinnon C

更新日期：2017-07-14 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：: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：:Membrane-bound pyrophosphatases (mPPases) regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in e.g. malaria. Yet only few nonphosphorus inhibitors have been reported so far. Here, we explore an isoxazole fragment hit, leading to the discovery of...

journal_title：ACS medicinal chemistry letters

authors： Johansson NG,Turku A,Vidilaseris K,Dreano L,Khattab A,Ayuso Pérez D,Wilkinson A,Zhang Y,Tamminen M,Grazhdankin E,Kiriazis A,Fishwick CWG,Meri S,Yli-Kauhaluoma J,Goldman A,Boije Af Gennäs G,Xhaard H

更新日期：2020-02-17 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：:A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure-activity relationships (SAR) in conjunction with X-ray crysta...

journal_title：ACS medicinal chemistry letters

authors： Tuttle JB,Anderson M,Bechle BM,Campbell BM,Chang C,Dounay AB,Evrard E,Fonseca KR,Gan X,Ghosh S,Horner W,James LC,Kim JY,McAllister LA,Pandit J,Parikh VD,Rago BJ,Salafia MA,Strick CA,Zawadzke LE,Verhoest PR

更新日期：2012-10-24 00:00:00

abstract：:GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategi...

journal_title：ACS medicinal chemistry letters

authors： Brooks CA,Barton LS,Behm DJ,Eidam HS,Fox RM,Hammond M,Hoang TH,Holt DA,Hilfiker MA,Lawhorn BG,Patterson JR,Stoy P,Roethke TJ,Ye G,Zhao S,Thorneloe KS,Goodman KB,Cheung M

更新日期：2019-07-15 00:00:00

abstract：:A series of novel aminopyridyl/pyrazinyl-substituted spiro[indoline-3,4'-piperidine]-2-ones were designed, synthesized, and tested in various in vitro/in vivo pharmacological and antitumor assays. 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1'-methylspiro[indoline-3,4'-piperidine]-2-one (compo...

journal_title：ACS medicinal chemistry letters

authors： Li J,Wu N,Tian Y,Zhang J,Wu S

更新日期：2013-07-12 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：:Stable isotope-mass spectrometry (MS)-based metabolomic profiling is a powerful technique for following changes in specific metabolite pool sizes and metabolic flux under various experimental conditions in a test organism or cell type. Here, we use a metabolomics approach to interrogate the mechanism of antibiotic act...

journal_title：ACS medicinal chemistry letters

authors： Prosser GA,de Carvalho LP

更新日期：2013-12-12 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：:All eight of the major active metabolites of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221, compound 1), an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 that has entered the clinic for the treatment of type 2 diabetes, were synthetically prepared and confirmed...

journal_title：ACS medicinal chemistry letters

authors： Li A,Yuan CC,Chow D,Chen M,Emery MG,Hale C,Zhang X,Subramanian R,St Jean DJ Jr,Komorowski R,Véniant M,Wang M,Fotsch C

更新日期：2011-09-13 00:00:00

abstract：:The endogenous amino acid, 5-aminolevulinic acid (5-ALA), has received significant attention as an imaging agent, including ongoing clinical trials for image-guided tumor resection due to its selective uptake and subsequent accumulation of the fluorescent protoporphyrin IX in tumor cells. Based on the widely reported ...

journal_title：ACS medicinal chemistry letters

authors： Pippin AB,Voll RJ,Li Y,Wu H,Mao H,Goodman MM

更新日期：2017-11-15 00:00:00