Identification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode.

abstract：:Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Comp...

journal_title：ACS medicinal chemistry letters

authors： Yu M,Wang Y,Zhu J,Bartberger MD,Canon J,Chen A,Chow D,Eksterowicz J,Fox B,Fu J,Gribble M,Huang X,Li Z,Liu JJ,Lo MC,McMinn D,Oliner JD,Osgood T,Rew Y,Saiki AY,Shaffer P,Yan X,Ye Q,Yu D,Zhao X,Zhou J,Ols

更新日期：2014-06-30 00:00:00

abstract：:A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, includ...

journal_title：ACS medicinal chemistry letters

authors： Truax VM,Zhao H,Katzman BM,Prosser AR,Alcaraz AA,Saindane MT,Howard RB,Culver D,Arrendale RF,Gruddanti PR,Evers TJ,Natchus MG,Snyder JP,Liotta DC,Wilson LJ

更新日期：2013-09-05 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：:Structure-activity relationship translation offers an expeditious means for discovery of new active series. This approach was applied to discover tetrahydroisoquinoline (THIQ)-based steroidomimetic microtubule disruptors. The two A-ring elements of a three-point steroidal pharmacophore were incorporated into a THIQ-ba...

journal_title：ACS medicinal chemistry letters

authors： Leese MP,Jourdan F,Dohle W,Kimberley MR,Thomas MP,Bai R,Hamel E,Ferrandis E,Potter BV

更新日期：2012-01-12 00:00:00

abstract：:Medicinal chemists have increasing opportunities to transition from the pharmaceutical industry to academic medical centers interested in translational research. This Viewpoint highlights some of the differences between these two cultures and strategies to succeed in academic drug discovery. ...

journal_title：ACS medicinal chemistry letters

authors： Barrow JC

更新日期：2019-04-15 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：:Cucurbit[7]uril (CB[7]) was found in vitro to sequester the neurotoxins MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP(+) (N-methyl-4-phenylpyridine). The CB[7]/neurotoxin host-guest complexes were studied in detail with (1)H NMR, electrospray ionization mass spectrometry, UV-visible spectroscopic titrati...

journal_title：ACS medicinal chemistry letters

authors： Li S,Chen H,Yang X,Bardelang D,Wyman IW,Wan J,Lee SM,Wang R

更新日期：2015-10-16 00:00:00

abstract：:The ring closing metathesis/transannular etherification approach to the englerin nucleus was adapted to provide two key intermediates for analogue synthesis: the 4-desmethyl Δ5,6 tricycle and the 4-oxo Δ5,6 tricycle. The former was elaborated to 4-desmethyl englerin A and the latter served as a common precursor for en...

journal_title：ACS medicinal chemistry letters

authors： Elliott DC,Beutler JA,Parker KA

更新日期：2017-06-06 00:00:00

abstract：:The National Institutes of Health (NIH) closure of the agency's Center for Regenerative Medicine (CRM), which focused on therapeutic development of induced pluripotent stem cells (iPS), was caused by the lack of progress in practical development of the iPSs for use in human therapies. As the NIH evaluates priorities i...

journal_title：ACS medicinal chemistry letters

authors： Maguire G

更新日期：2014-10-08 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：:Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3β, allow t...

journal_title：ACS medicinal chemistry letters

authors： Wang Y,Wach JY,Sheehan P,Zhong C,Zhan C,Harris R,Almo SC,Bishop J,Haggarty SJ,Ramek A,Berry KN,O'Herin C,Koehler AN,Hung AW,Young DW

更新日期：2016-07-14 00:00:00

abstract：:Translational readthrough-inducing drugs (TRIDs) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we repor...

journal_title：ACS medicinal chemistry letters

authors： Tutone M,Pibiri I,Perriera R,Campofelice A,Culletta G,Melfi R,Pace A,Almerico AM,Lentini L

更新日期：2020-02-18 00:00:00

abstract：:A series of N-(3-ethynyl-2,4-difluorophenyl)sulfonamides were identified as new selective Raf inhibitors. The compounds potently inhibit B-Raf(V600E) with low nanomolar IC50 values and exhibit excellent target specificity in a selectivity profiling investigation against 468 kinases. They strongly suppress proliferatio...

journal_title：ACS medicinal chemistry letters

authors： Li Y,Cheng H,Zhang Z,Zhuang X,Luo J,Long H,Zhou Y,Xu Y,Taghipouran R,Li D,Patterson A,Smaill J,Tu Z,Wu D,Ren X,Ding K

更新日期：2015-03-18 00:00:00

abstract：:Current treatment of toxoplasmosis targets the parasite's folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and h...

journal_title：ACS medicinal chemistry letters

authors： Welsch ME,Zhou J,Gao Y,Yan Y,Porter G,Agnihotri G,Li Y,Lu H,Chen Z,Thomas SB

更新日期：2016-09-17 00:00:00

abstract：:Computer-aided drug design could benefit from a greater understanding of how errors arise and propagate in biomolecular modeling. With such knowledge, model predictions could be associated with quantitative estimates of their uncertainty. In addition, novel algorithms could be designed to proactively reduce prediction...

journal_title：ACS medicinal chemistry letters

authors： Faver JC,Ucisik MN,Yang W,Merz KM Jr

更新日期：2013-09-12 00:00:00

abstract：:Two rigid analogues of 5-ethylindolobenzazepinone 4, a potent cytotoxic agent and inhibitor of tubulin polymerization, were prepared. The first was the indane derivative 5, in which the ethyl group is attached to the benzo moiety. The second was the pyrrolidine analogue 6, in which the ethyl chain was bound to the lac...

journal_title：ACS medicinal chemistry letters

authors： Pons V,Beaumont S,Tran Huu Dau ME,Iorga BI,Dodd RH

更新日期：2011-06-05 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：: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：: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：:Selective activation of the M1 muscarinic receptor via positive allosteric modulation represents an approach to treat the cognitive decline in patients with Alzheimer's disease. A series of amides were examined as a replacement for the carboxylic acid moiety in a class of quinolizidinone carboxylic acid M1 muscarinic ...

journal_title：ACS medicinal chemistry letters

authors： Kuduk SD,Chang RK,Greshock TJ,Ray WJ,Ma L,Wittmann M,Seager MA,Koeplinger KA,Thompson CD,Hartman GD,Bilodeau MT

更新日期：2012-10-13 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：:SMARTCyp is an in silico method that predicts the sites of cytochrome P450-mediated metabolism of druglike molecules. The method is foremost a reactivity model, and as such, it shows a preference for predicting sites that are metabolized by the cytochrome P450 3A4 isoform. SMARTCyp predicts the site of metabolism dire...

journal_title：ACS medicinal chemistry letters

authors： Rydberg P,Gloriam DE,Zaretzki J,Breneman C,Olsen L

更新日期：2010-03-15 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：: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 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：: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：: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：:Here, we predicted the potential halogen bonding interaction between compound 2 and the 5-hydroxytryptamine 2B (5-HT2B) receptor and systematically assessed this interaction via structure-activity relationship analysis and molecular dynamics simulations. A physics-based computational protocol was then developed to fur...

journal_title：ACS medicinal chemistry letters

authors： Zhou Y,Wang Y,Li P,Huang XP,Qi X,Du Y,Huang N

更新日期：2018-10-01 00:00:00

abstract：:A series of potent and selective β1-adrenoreceptor ligands were identified (IC50 range, 0.04-0.25 nM; β1/β2 selectivity range, 65-450-fold), labeled with the PET radioisotope fluorine-18 and evaluated in normal Sprague-Dawley rats. Tissue distribution studies demonstrated uptake of each radiotracers from the blood poo...

journal_title：ACS medicinal chemistry letters

authors： Radeke HS,Purohit A,Harris TD,Hanson K,Jones R,Hu C,Yalamanchili P,Hayes M,Yu M,Guaraldi M,Kagan M,Azure M,Cdebaca M,Robinson S,Casebier D

更新日期：2011-07-22 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