Structural Approach to Assessing the Innovativeness of New Drugs Finds Accelerating Rate of Innovation.

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：: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 new prosthetic group referred to as the triazole appending agent (TAAG) was developed as a means to prepare targeted radioiodine-based molecular imaging and therapy agents. Tributyltin-TAAG and the fluorous analogue were synthesized in high yield using simple click chemistry and the products labeled in greater than ...

journal_title：ACS medicinal chemistry letters

authors： Darwish A,Blacker M,Janzen N,Rathmann SM,Czorny S,Hillier SM,Joyal JL,Babich JW,Valliant JF

更新日期：2012-02-18 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：: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：: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：: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：:A series of novel antifungal carboline derivatives was designed and synthesized, which showed broad-spectrum antifungal activity. Particularly, compound C38 showed comparable in vitro antifungal activity to fluconazole without toxicity to human embryonic lung cells. It also exhibited good fungicidal activity against b...

journal_title：ACS medicinal chemistry letters

authors： Wang S,Wang Y,Liu W,Liu N,Zhang Y,Dong G,Liu Y,Li Z,He X,Miao Z,Yao J,Li J,Zhang W,Sheng C

更新日期：2014-02-13 00:00:00

abstract：:Structural modifications to the coumarin core and benzamide side chain of novobiocin have successfully transformed the natural product from a selective DNA gyrase inhibitor into a potent inhibitor of the Hsp90 C-terminus. However, no SAR studies have been conducted on the noviose appendage, which represents the rate-l...

journal_title：ACS medicinal chemistry letters

authors： Zhao H,Kusuma BR,Blagg BS

更新日期：2010-07-13 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：: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：: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：:Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alt...

journal_title：ACS medicinal chemistry letters

authors： Popovici-Muller J,Lemieux RM,Artin E,Saunders JO,Salituro FG,Travins J,Cianchetta G,Cai Z,Zhou D,Cui D,Chen P,Straley K,Tobin E,Wang F,David MD,Penard-Lacronique V,Quivoron C,Saada V,de Botton S,Gross S,Dang L,Y

更新日期：2018-01-19 00:00:00

abstract：:Nonsense mutations introduce a premature termination codon (PTC) and are the underlying cause of multiple rare genetic diseases and cancers. Although certain aminoglycosides bind to eukaryotic ribosomes enabling incorporation of an amino acid at the PTC and formation of full-length protein, they are inefficient and to...

journal_title：ACS medicinal chemistry letters

authors： Rabea SM,Baradaran-Heravi A,Balgi AD,Krause A,Hosseini Farahabadi S,Roberge M,Grierson DS

更新日期：2019-04-09 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

abstract：:By employing a phenotypic screen, a set of compounds, exemplified by 1, were identified which potentiate the ability of histone deacetylase inhibitor vorinostat to reverse HIV latency. Proteome enrichment followed by quantitative mass spectrometric analysis employing a modified analogue of 1 as affinity bait identifie...

journal_title：ACS medicinal chemistry letters

authors： Bukhtiyarova M,Cook EM,Hancock PJ,Hruza AW,Shaw AW,Adam GC,Barnard RJO,McKenna PM,Holloway MK,Bell IM,Carroll S,Cornella-Taracido I,Cox CD,Kutchukian PS,Powell DA,Strickland C,Trotter BW,Tudor M,Wolkenberg S,Li J,

更新日期：2020-12-23 00:00:00

abstract：:PAR2 antagonists have potential for treating inflammatory, respiratory, gastrointestinal, neurological, and metabolic disorders, but few antagonists are known. Derivatives of GB88 (3) suggest that all four of its components bind at distinct PAR2 sites with the isoxazole, cyclohexylalanine, and isoleucine determining a...

journal_title：ACS medicinal chemistry letters

authors： Yau MK,Liu L,Suen JY,Lim J,Lohman RJ,Jiang Y,Cotterell AJ,Barry GD,Mak JY,Vesey DA,Reid RC,Fairlie DP

更新日期：2016-10-10 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：: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：: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：: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 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：:The multistep preparation of (11)C-levetiracetam ((11)C-LEV) was carried out by a one-pot radiosynthesis with 8.3 ± 1.6% (n = 8) radiochemical yield in 50 ± 5.0 min. Briefly, the propionaldehyde was converted to propan-1-imine in situ as labeling precursor by incubation with ammonia. Without further separation, the im...

journal_title：ACS medicinal chemistry letters

authors： Cai H,Mangner TJ,Muzik O,Wang MW,Chugani DC,Chugani HT

更新日期：2014-08-19 00:00:00

abstract：:A competitive fluorescence polarization (FP) assay is reported for determining binding affinities of probe molecules with the pseudokinase JAK2 JH2 allosteric site. The syntheses of the fluorescent 5 and 6 used in the assay are reported as well as Kd results for 10 compounds, including JNJ7706621, NVP-BSK805, and filg...

journal_title：ACS medicinal chemistry letters

authors： Newton AS,Deiana L,Puleo DE,Cisneros JA,Cutrona KJ,Schlessinger J,Jorgensen WL

更新日期：2017-05-17 00:00:00

abstract：:Bacterial RNA polymerase (RNAP) is essential for transcription and is an antibacterial target for small molecule inhibitors. The binding region of myxopyronin B (MyxB), a bacterial RNAP inhibitor, offers the possibility of new inhibitor design. The molecular design program SPROUT has been used in conjunction with the ...

journal_title：ACS medicinal chemistry letters

authors： McPhillie MJ,Trowbridge R,Mariner KR,O'Neill AJ,Johnson AP,Chopra I,Fishwick CW

更新日期：2011-07-29 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：:We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (K i = 5.1 nM). We also present a model...

journal_title：ACS medicinal chemistry letters

authors： Chelliah MV,Eagen K,Guo Z,Chackalamannil S,Xia Y,Tsai H,Greenlee WJ,Ahn HS,Kurowski S,Boykow G,Hsieh Y,Chintala M

更新日期：2014-03-11 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：: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：:To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists ...

journal_title：ACS medicinal chemistry letters

authors： Ogawa S,Watanabe T,Sugimoto I,Moriyuki K,Goto Y,Yamane S,Watanabe A,Tsuboi K,Kinoshita A,Kigoshi H,Tani K,Maruyama T

更新日期：2016-01-04 00:00:00