Importance of a 4-Alkyl Substituent for Activity in the Englerin Series.

abstract：:An efficient method for the reconstruction of the 9-dihydroerythromycin A macrolactone skeleton has been established. The key steps are oxidative cleavage at the 11,12-position and reconstruction after insertion of an appropriate functionalized amino alcohol. Novel 15-membered macrolides, we named as "11a-azalides", w...

journal_title：ACS medicinal chemistry letters

authors： Sugimoto T,Tanikawa T

更新日期：2010-12-30 00:00:00

abstract：:A new class of potent matrix metalloproteinase (MMP) inhibitors designed by structure-based optimization of the well-known arylsulfonamide scaffold is presented. Molecules show an ethylene linker connecting the sulfonamide group with the P1' aromatic portion and a d-proline residue bearing the zinc-binding group. The ...

journal_title：ACS medicinal chemistry letters

authors： Mori M,Massaro A,Calderone V,Fragai M,Luchinat C,Mordini A

更新日期：2013-05-14 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：: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：:We report here the total synthesis of B-973 (five steps), a recently identified α7 nAChR ago-PAM, its enantiomeric resolution, and its electrophysiological characterization in Xenopus oocytes to identify (-)-B-973B as the bioactive enantiomer. The asymmetric synthesis of B-973B was accomplished in 99% ee, and X-ray cr...

journal_title：ACS medicinal chemistry letters

authors： Garai S,Raja KS,Papke RL,Deschamps JR,Damaj MI,Thakur GA

更新日期：2018-10-11 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：: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：: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：:Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for the folding and maturation of client proteins that are associated with all ten hallmarks of cancer. Hsp90 N-terminal pan inhibitors have experienced unfavorable results in clinical trials due to induction of the heat shock response (HSR), a...

journal_title：ACS medicinal chemistry letters

authors： Pugh KW,Zhang Z,Wang J,Xu X,Munthali V,Zuo A,Blagg BSJ

更新日期：2020-06-11 00:00:00

abstract：:[This corrects the article DOI: 10.1021/acsmedchemlett.9b00612.]. ...

journal_title：ACS medicinal chemistry letters

authors： Kaiser TM,Dentmon ZW,Dalloul CE,Sharma SK,Liotta DC

更新日期：2020-06-24 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：: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：:Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the la...

journal_title：ACS medicinal chemistry letters

authors： Campbell JE,Kuntz KW,Knutson SK,Warholic NM,Keilhack H,Wigle TJ,Raimondi A,Klaus CR,Rioux N,Yokoi A,Kawano S,Minoshima Y,Choi HW,Porter Scott M,Waters NJ,Smith JJ,Chesworth R,Moyer MP,Copeland RA

更新日期：2015-03-04 00:00:00

abstract：:P-glycoprotein (Pgp) is capable of recognizing and transporting a wide range of chemically diverse compounds in vivo. Overcoming Pgp-mediated efflux can represent a significant challenge when penetration into the central nervous system is required or within the context of developing anticancer therapies. While numerou...

journal_title：ACS medicinal chemistry letters

authors： Gunaydin H,Weiss MM,Sun Y

更新日期：2012-11-06 00:00:00

abstract：:Two novel benzofuran derivatives coupled with (99m)Tc complexes were tested as probes for imaging cerebral β-amyloid plaques using single photon emission tomography. Although both derivatives bound to Aβ(1-42) aggregates, (99m)Tc-BAT-BF showed higher affinity than (99m)Tc-MAMA-BF. In sections of brain tissue from an a...

journal_title：ACS medicinal chemistry letters

authors： Ono M,Fuchi Y,Fuchigami T,Kobashi N,Kimura H,Haratake M,Saji H,Nakayama M

更新日期：2010-08-02 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：:A series of structurally diverse azaspirodecanone and spirooxazolidinone analogues were designed and synthesized as potent and selective somatostatin receptor subtype 5 (SSTR5) antagonists. Four optimized compounds each representing a subseries showed improvement in their metabolic stability and pharmacokinetic profil...

journal_title：ACS medicinal chemistry letters

authors： Liu W,Hussain Z,Zang Y,Sweis RF,Romero FA,Finke PE,Moningka R,Bao J,Plotkin MA,Shang J,Dingley KH,Salituro G,Murphy BA,Howard AD,Ujjainwalla F,Wood HB,Duffy JL

更新日期：2018-10-05 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：: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：: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：: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：:Insulin-regulated aminopeptidase (IRAP) is a transmembrane zinc metallopeptidase with many important biological functions and an emerging pharmacological target. Although previous structural studies have given insight on how IRAP recognizes linear peptides, how it recognizes its physiological cyclic ligands remains el...

journal_title：ACS medicinal chemistry letters

authors： Mpakali A,Saridakis E,Giastas P,Maben Z,Stern LJ,Larhed M,Hallberg M,Stratikos E

更新日期：2020-06-02 00:00:00

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：: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：:S-Nitrosoglutathione reductase (GSNOR) regulates S-nitrosothiols (SNOs) and nitric oxide (NO) in vivo through catabolism of S-nitrosoglutathione (GSNO). GSNOR and the anti-inflammatory and smooth muscle relaxant activities of SNOs, GSNO, and NO play significant roles in pulmonary, cardiovascular, and gastrointestinal ...

journal_title：ACS medicinal chemistry letters

authors： Sun X,Wasley JW,Qiu J,Blonder JP,Stout AM,Green LS,Strong SA,Colagiovanni DB,Richards JP,Mutka SC,Chun L,Rosenthal GJ

更新日期：2011-03-11 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：:Mitragyna speciosa, also known as kratom, has the potential meet the need for pain medications that lack the addictiveness and overdose risk of classical opioid analgesics, such as morphine. This need is urgent because opioid addiction and overdose deaths have risen throughout diverse segments of U.S. society. Some op...

journal_title：ACS medicinal chemistry letters

authors： Halpenny GM

更新日期：2017-08-08 00:00:00

abstract：:The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be n...

journal_title：ACS medicinal chemistry letters

authors： Goodwin NC,Cianchetta G,Burgoon HA,Healy J,Mabon R,Strobel ED,Allen J,Wang S,Hamman BD,Rawlins DB

更新日期：2014-08-07 00:00:00

abstract：:We have developed a novel albumin-binding prodrug of doxorubicin that incorporates p-aminobenzyloxycarbonyl (PABC) as a 1,6 self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, as a substrate for the prostate-specific antigen (PSA) that is overexpressed in prostate carcinoma and represe...

journal_title：ACS medicinal chemistry letters

authors： Elsadek B,Graeser R,Warnecke A,Unger C,Saleem T,El-Melegy N,Madkor H,Kratz F

更新日期：2010-05-26 00:00:00

abstract：:WaterMap and MM-GB/SA scoring methods were applied to an extensive congeneric series of small-molecule SRC inhibitors with high-quality enzyme data and well characterized binding modes to compare the performance of these scoring methods in this data set and to provide insight into the relative strengths of each method...

journal_title：ACS medicinal chemistry letters

authors： Kohlmann A,Zhu X,Dalgarno D

更新日期：2012-01-06 00:00:00