Discovery of a GPR40 Superagonist: The Impact of Aryl Propionic Acid α-Fluorination.

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：: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：: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：: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：:Carbazoles represent a family of tricyclic compounds that widely appeared in nature. Numerous studies have revealed a diverse array of bioactivity associated with this scaffold. In the present study, a novel and highly efficient methodology for preparing 1,3-dihydroxy-2-carboxycarbazole from indole-3-acetic acid and M...

journal_title：ACS medicinal chemistry letters

authors： Liu K,Zhang S

更新日期：2015-07-10 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：: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：:To search for effective cancer vaccines based on sTn, a sialylated tumor-associated carbohydrate antigen (sialo-TACA) expressed by a number of tumors, four unnatural N-acyl sTn derivatives, including 5'-N-p-methylphenylacetyl sTn (sTnNMePhAc), 5'-N-p-methoxylphenylacetyl sTn (sTnNMeOPhAc), 5'-N-p-acetylphenylacetyl sT...

journal_title：ACS medicinal chemistry letters

authors： Wang Q,Guo Z

更新日期：2011-05-12 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：:Representative d-amino acid oxidase (DAAO) inhibitors were subjected to in vitro liver microsomal stability tests in the absence or presence of uridine diphosphate glucuronic acid (UDPGA). While carboxylate-based DAAO inhibitors displayed little glucuronidation, most DAAO inhibitors containing α-hydroxycarbonyl moiety...

journal_title：ACS medicinal chemistry letters

authors： Zimmermann SC,Rais R,Alt J,Burzynski C,Slusher BS,Tsukamoto T

更新日期：2014-10-21 00:00:00

abstract：:Protein kinases are key regulators that govern complex cellular processes. Dysregulation of kinase signaling is associated in many human diseases, particularly cancers and developmental and metabolic disorders. Tyrosine kinase inhibitors have achieved great success in molecular targeted therapies for cancer and now is...

journal_title：ACS medicinal chemistry letters

authors： Cui JJ

更新日期：2014-03-06 00:00:00

abstract：:Design and synthesis of prodrugs of promising drug candidates represents a valid strategy to overcome the lack of favorable ADME properties, in particular aqueous solubility and bioavailability. We report herein the successful application of this strategy with two representative pyrazolo[3,4-d]pyrimidine derivatives (...

journal_title：ACS medicinal chemistry letters

authors： Vignaroli G,Zamperini C,Dreassi E,Radi M,Angelucci A,Sanità P,Crespan E,Kissova M,Maga G,Schenone S,Musumeci F,Botta M

更新日期：2013-05-20 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：: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：: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：:Use of DNA-encoded libraries (DELs) in the pharmaceutical industry has rapidly increased. We discuss what to expect when you run a DEL screen and contemplate guidelines for library design. Additionally, we consider some visionary work and extrapolate to the future. ...

journal_title：ACS medicinal chemistry letters

authors： Satz AL

更新日期：2018-04-17 00:00:00

abstract：:A series of novel selenides bearing benzenesulfonamide moieties was synthesized and investigated for their inhibition on six human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms such as the physiologically relevant hCA I, II, VA, VB, VII, and IX and the X-ray complex in adduct with hCA II for some of them investigat...

journal_title：ACS medicinal chemistry letters

authors： Angeli A,di Cesare Mannelli L,Trallori E,Peat TS,Ghelardini C,Carta F,Supuran CT

更新日期：2018-04-09 00:00:00

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：:A series of urea/thiourea substituted benzoxaboroles was investigated for the inhibition of the three carbonic anhydrases encoded by Vibrio cholerae (VchCAα, VchCAβ, and VchCAγ). In particular, benzoxaborole derivatives were here first assayed for the inhibition of a γ-class CA, extending the panel of CA classes that ...

journal_title：ACS medicinal chemistry letters

authors： Bonardi A,Nocentini A,Cadoni R,Del Prete S,Dumy P,Capasso C,Gratteri P,Supuran CT,Winum JY

更新日期：2020-09-09 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：: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：:Hsp90 C-terminal inhibitors represent a novel and alternative chemotherapeutic approach for the treatment of cancer. Novobiocin was the first natural product identified as an Hsp90 C-terminal inhibitor; however, it manifests poor antiproliferative activity. In contrast to N-terminal inhibitors, novobiocin does not ind...

journal_title：ACS medicinal chemistry letters

authors： Garg G,Zhao H,Blagg BS

更新日期：2014-12-12 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：:In this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFRL858R/T790M/C797S. One of the most promising compounds, 25g, inhibited the enzymatic activity of EGFRL858R/T790M/C797S with an IC50 value of 2.2 nM. Cell proliferation assa...

journal_title：ACS medicinal chemistry letters

authors： Li Q,Zhang T,Li S,Tong L,Li J,Su Z,Feng F,Sun D,Tong Y,Wang X,Zhao Z,Zhu L,Ding J,Li H,Xie H,Xu Y

更新日期：2019-05-22 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：:A focused multiply N-methylated library of a cyclic hexapeptidic somatostatin analogue: MK678 cyclo(-MeAYwKVF-) was generated, which resulted in the unexpected observation of an efficacious tetra-N-methylated analogue, cyclo(-MeAYMewMeKVMeF-) with a potent inhibitory action on sensory neuropeptide release in vitro and...

journal_title：ACS medicinal chemistry letters

authors： Chatterjee J,Laufer B,Beck JG,Helyes Z,Pintér E,Szolcsányi J,Horvath A,Mandl J,Reubi JC,Kéri G,Kessler H

更新日期：2011-04-04 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：:We describe the discovery of three structurally differentiated potent and selective MTH1 inhibitors and their subsequent use to investigate MTH1 as an oncology target, culminating in target (in)validation. Tetrahydronaphthyridine 5 was rapidly identified as a highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystalli...

journal_title：ACS medicinal chemistry letters

authors： Farand J,Kropf JE,Blomgren P,Xu J,Schmitt AC,Newby ZE,Wang T,Murakami E,Barauskas O,Sudhamsu J,Feng JY,Niedziela-Majka A,Schultz BE,Schwartz K,Viatchenko-Karpinski S,Kornyeyev D,Kashishian A,Fan P,Chen X,Lansdon EB

更新日期：2019-11-19 00:00:00

abstract：:A series of 3-deoxy-3-N-arylated-β-d-galactoside and -guloside derivatives have been synthesized by cesium fluoride/trimetylsilylaryl triflate-mediated benzyne generation and N-arylation of 3-deoxy-3-amino-β-d-galactosides and -gulosides, respectively. Evaluation as ligands to galectin-1, 2, 3, 4N (N-terminal domain),...

journal_title：ACS medicinal chemistry letters

authors： Mahanti M,Pal KB,Sundin AP,Leffler H,Nilsson UJ

更新日期：2019-12-04 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