Optimization of Preclinical Metabolism for Somatostatin Receptor Subtype 5-Selective Antagonists.

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：:An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared to the corresponding 4-phenylpiperazine analogue. To explore a possible rein...

journal_title：ACS medicinal chemistry letters

authors： Liégeois JF,Lespagnard M,Meneses Salas E,Mangin F,Scuvée-Moreau J,Dilly S

更新日期：2014-01-29 00:00:00

abstract：:Toxoplasma gondii causes a prevalent human infection for which only the acute stage has an FDA-approved therapy. To find inhibitors of both the acute stage parasites and the persistent cyst stage that causes a chronic infection, we repurposed a compound library containing known inhibitors of parasitic hexokinase, the ...

journal_title：ACS medicinal chemistry letters

authors： Khalifa MM,Martorelli Di Genova B,McAlpine SG,Gallego-Lopez GM,Stevenson DM,Rozema SD,Monaghan NP,Morris JC,Knoll LJ,Golden JE

更新日期：2020-10-13 00:00:00

abstract：:Water-soluble cyclodextrin (CyD) complexed with porphyrin derivatives with different substituents in the meso-positions showed different photodynamic activities toward cancer cells under illumination at wavelengths over 600 nm, the most suitable wavelengths for photodynamic therapy (PDT). In particular, aniline- and p...

journal_title：ACS medicinal chemistry letters

authors： Ikeda A,Satake S,Mae T,Ueda M,Sugikawa K,Shigeto H,Funabashi H,Kuroda A

更新日期：2017-04-19 00:00:00

abstract：:A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust ph...

journal_title：ACS medicinal chemistry letters

authors： Walsh SP,Shahripour A,Tang H,Teumelsan N,Frie J,Zhu Y,Priest BT,Swensen AM,Liu J,Margulis M,Visconti R,Weinglass A,Felix JP,Brochu RM,Bailey T,Thomas-Fowlkes B,Alonso-Galicia M,Zhou X,Pai LY,Corona A,Hampton C,H

更新日期：2015-05-07 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：: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：:Measuring innovation in the pharmaceutical industry is challenging. Counts of new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) are commonly used, but this measure only gauges quantity not innovativeness. A new indicator of innovation for small molecule and peptide drugs based on structu...

journal_title：ACS medicinal chemistry letters

authors： Wills TJ,Lipkus AH

更新日期：2020-09-10 00:00:00

abstract：:The effects of opioids in the central nervous system (CNS) provide significant benefit in the treatment of pain but can also lead to physical dependence and addiction, which has contributed to a growing opioid epidemic in the United States. Gastrointestinal dysfunction is an additional serious consequence of opioid us...

journal_title：ACS medicinal chemistry letters

authors： Long DD,Armstrong SR,Beattie DT,Campbell CB,Church TJ,Colson PJ,Dalziel SM,Jacobsen JR,Jiang L,Obedencio GP,Rapta M,Saito D,Stergiades I,Tsuruda PR,Van Dyke PM,Vickery RG

更新日期：2019-11-26 00:00:00

abstract：:The atypical chemokine receptor CXCR7 has been studied in various disease settings including immunological diseases and heart disease. Efforts to elucidate the role of CXCR7 have been limited by the lack of suitable chemical tools with a range of pharmacological profiles. A high-throughput screen was conducted to disc...

journal_title：ACS medicinal chemistry letters

authors： Menhaji-Klotz E,Ward J,Brown JA,Loria PM,Tan C,Hesp KD,Riccardi KA,Litchfield J,Boehm M

更新日期：2020-05-14 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：:B-cell lymphoma 6 (BCL6) is a transcriptional repressor frequently deregulated in lymphoid malignancies. BCL6 engages with number of corepressors, and these protein-protein interactions are being explored as a strategy for drug development. Here, we report the development of an irreversible BCL6 inhibitor TMX-2164 tha...

journal_title：ACS medicinal chemistry letters

authors： Teng M,Ficarro SB,Yoon H,Che J,Zhou J,Fischer ES,Marto JA,Zhang T,Gray NS

更新日期：2020-04-03 00:00:00

abstract：:The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization ...

journal_title：ACS medicinal chemistry letters

authors： Cee VJ,Chavez F Jr,Herberich B,Lanman BA,Pettus LH,Reed AB,Wu B,Wurz RP,Andrews KL,Chen J,Hickman D,Laszlo J 3rd,Lee MR,Guerrero N,Mattson BK,Nguyen Y,Mohr C,Rex K,Sastri CE,Wang P,Wu Q,Wu T,Xu Y,Zhou Y,Wi

更新日期：2016-02-12 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：:Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of ...

journal_title：ACS medicinal chemistry letters

authors： Szokol B,Gyulavári P,Kurkó I,Baska F,Szántai-Kis C,Greff Z,Orfi Z,Peták I,Pénzes K,Torka R,Ullrich A,Orfi L,Vántus T,Kéri G

更新日期：2014-01-30 00:00:00

abstract：:Structure-based design methods commonly used in medicinal chemistry rely on a three-dimensional representation of the receptor. However, few crystal structures are solved in comparison with the huge number of pharmaceutical targets. This often renders homology models the only information available. It is particularly ...

journal_title：ACS medicinal chemistry letters

authors： Levoin N,Calmels T,Krief S,Danvy D,Berrebi-Bertrand I,Lecomte JM,Schwartz JC,Capet M

更新日期：2011-02-11 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：:Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compo...

journal_title：ACS medicinal chemistry letters

authors： Hoegenauer K,Soldermann N,Stauffer F,Furet P,Graveleau N,Smith AB,Hebach C,Hollingworth GJ,Lewis I,Gutmann S,Rummel G,Knapp M,Wolf RM,Blanz J,Feifel R,Burkhart C,Zécri F

更新日期：2016-06-02 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：:Herein, we report the structure-activity relationships within a series of mGlu7 PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (Kps > 1 and Kp,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu...

journal_title：ACS medicinal chemistry letters

authors： Abe M,Seto M,Gogliotti RG,Loch MT,Bollinger KA,Chang S,Engelberg EM,Luscombe VB,Harp JM,Bubser M,Engers DW,Jones CK,Rodriguez AL,Blobaum AL,Conn PJ,Niswender CM,Lindsley CW

更新日期：2017-09-01 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：:Re(I) tricarbonyl polypyridine-based complexes are particularly attractive metal complexes in the field of inorganic chemical biology due to their luminescent properties, ease of conjugation to targeting biomolecules, and the possibility to prepare their "hot" (99m)Tc analogues for radioimaging. In this study, we prep...

journal_title：ACS medicinal chemistry letters

authors： Leonidova A,Pierroz V,Adams LA,Barlow N,Ferrari S,Graham B,Gasser G

更新日期：2014-05-15 00:00:00

abstract：:This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described. ...

journal_title：ACS medicinal chemistry letters

authors： Miller CP,Shomali M,Lyttle CR,O'Dea LS,Herendeen H,Gallacher K,Paquin D,Compton DR,Sahoo B,Kerrigan SA,Burge MS,Nickels M,Green JL,Katzenellenbogen JA,Tchesnokov A,Hattersley G

更新日期：2010-12-02 00:00:00

abstract：:The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORγt with 1a, an analogue of the known pip...

journal_title：ACS medicinal chemistry letters

authors： Nakajima R,Oono H,Sugiyama S,Matsueda Y,Ida T,Kakuda S,Hirata J,Baba A,Makino A,Matsuyama R,White RD,Wurz RΡ,Shin Y,Min X,Guzman-Perez A,Wang Z,Symons A,Singh SK,Mothe SR,Belyakov S,Chakrabarti A,Shuto S

更新日期：2020-02-27 00:00:00

abstract：:Cellular proteins that fail to fold properly result in inactive or disfunctional proteins that can have toxic functions. The unfolded protein response (UPR) is a two-tiered cellular mechanism initiated by eukaryotic cells that have accumulated misfolded proteins within the endoplasmic reticulum (ER). An adaptive pathw...

journal_title：ACS medicinal chemistry letters

authors： Flaherty DP,Miller JR,Garshott DM,Hedrick M,Gosalia P,Li Y,Milewski M,Sugarman E,Vasile S,Salaniwal S,Su Y,Smith LH,Chung TD,Pinkerton AB,Aubé J,Callaghan MU,Golden JE,Fribley AM,Kaufman RJ

更新日期：2014-10-29 00:00:00

abstract：:Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design ...

journal_title：ACS medicinal chemistry letters

authors： Wang L,Doherty GA,Judd AS,Tao ZF,Hansen TM,Frey RR,Song X,Bruncko M,Kunzer AR,Wang X,Wendt MD,Flygare JA,Catron ND,Judge RA,Park CH,Shekhar S,Phillips DC,Nimmer P,Smith ML,Tahir SK,Xiao Y,Xue J,Zhang H,Le PN

更新日期：2020-03-30 00:00:00

abstract：:ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/...

journal_title：ACS medicinal chemistry letters

authors： Tang H,Zhu Y,Teumelsan N,Walsh SP,Shahripour A,Priest BT,Swensen AM,Felix JP,Brochu RM,Bailey T,Thomas-Fowlkes B,Pai LY,Hampton C,Corona A,Hernandez M,Metzger J,Forrest M,Zhou X,Owens K,Tong V,Parmee E,Roy S,K

更新日期：2016-05-12 00:00:00

abstract：:A novel two-step in situ method for targeted antitumor drug release by supramolecular assembly (Fc-CPT@HACD) was constructed using camptothecin prodrug (Fc-CPT) and β-cyclodextrin (β-CD)-modified hyaluronic acid (HACD). Benefiting from the overexpressed H2O2 and glutathione (GSH) in tumor cells, Fc-CPT@HACD can be dis...

journal_title：ACS medicinal chemistry letters

authors： Fu HG,Chen Y,Yu Q,Liu Y

更新日期：2020-05-18 00:00:00

abstract：:Protein thermal shift assays (TSAs) provide a means for characterizing target engagement through ligand-induced thermal stabilization. Although these assays are widely utilized for screening libraries and validating hits in drug discovery programs, they can impose encumbering operational requirements, such as the avai...

journal_title：ACS medicinal chemistry letters

authors： Dart ML,Machleidt T,Jost E,Schwinn MK,Robers MB,Shi C,Kirkland TA,Killoran MP,Wilkinson JM,Hartnett JR,Zimmerman K,Wood KV

更新日期：2018-04-16 00:00:00

abstract：:A focused high throughput screening for GPR139 was completed for a select 100K compounds, and new agonist leads were identified. Subsequent analysis and structure-activity relationship studies identified (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide 7c as a potent and selective agonist of hGPR139 with ...

journal_title：ACS medicinal chemistry letters

authors： Dvorak CA,Coate H,Nepomuceno D,Wennerholm M,Kuei C,Lord B,Woody D,Bonaventure P,Liu C,Lovenberg T,Carruthers NI

更新日期：2015-07-20 00:00:00