Discovery of G Protein-Biased EP2 Receptor Agonists.

abstract：:Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with...

journal_title：ACS medicinal chemistry letters

authors： Feng Y,Park H,Bauer L,Ryu JC,Yoon SO

更新日期：2020-12-13 00:00:00

abstract：:Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite P. yoelii (Py) as well as hypnozoites of the simian parasite P. cynomolgi (Pc). We applied these various assays to the cell-based lea...

journal_title：ACS medicinal chemistry letters

authors： Zou B,Nagle A,Chatterjee AK,Leong SY,Tan LJ,Sim WL,Mishra P,Guntapalli P,Tully DC,Lakshminarayana SB,Lim CS,Tan YC,Abas SN,Bodenreider C,Kuhen KL,Gagaring K,Borboa R,Chang J,Li C,Hollenbeck T,Tuntland T,Zeeman A

更新日期：2014-07-06 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：:A series of novel N-acyclic uracil analogs with linear, branched, aromatic, and cyclopropyl-alkynyl as well as heteroaryl moieties at C-5 were prepared using palladium catalyzed Sonogashira and Stille cross-coupling and evaluated against malignant tumor cell lines. C-5-Furan-2-yl uracil derivative 6 was shown to be mo...

journal_title：ACS medicinal chemistry letters

authors： Meščić A,Harej A,Klobučar M,Glavač D,Cetina M,Pavelić SK,Raić-Malić S

更新日期：2015-10-05 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 medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in o...

journal_title：ACS medicinal chemistry letters

authors： Yue EW,Li YL,Douty B,He C,Mei S,Wayland B,Maduskuie T,Falahatpisheh N,Sparks RB,Polam P,Zhu W,Glenn J,Feng H,Zhang K,Li Y,He X,Katiyar K,Covington M,Feldman P,Shin N,Wang KH,Diamond S,Li Y,Koblish HK,Hall

更新日期：2019-10-17 00:00:00

abstract：:Bacterial resistance has become a worldwide concern after the emergence of metallo-β-lactamases (MBLs). They represent one of the major mechanisms of bacterial resistance against beta-lactam antibiotics. Among MBLs, New Delhi metallo-β-lactamase-1 NDM-1, the most prevalent type, is extremely efficient in inactivating ...

journal_title：ACS medicinal chemistry letters

authors： Spyrakis F,Celenza G,Marcoccia F,Santucci M,Cross S,Bellio P,Cendron L,Perilli M,Tondi D

更新日期：2017-11-26 00:00:00

abstract：:The Hu family of RNA-binding proteins plays a crucial role in post-transcriptional processes; indeed, Hu-RNA complexes are involved in various dysfunctions (i.e., inflammation, neurodegeneration, and cancer) and have been recently proposed as promising therapeutic targets. Intrigued by this concept, our research effor...

journal_title：ACS medicinal chemistry letters

authors： Volpe SD,Listro R,Parafioriti M,Di Giacomo M,Rossi D,Ambrosio FA,Costa G,Alcaro S,Ortuso F,Hirsch AKH,Vasile F,Collina S

更新日期：2020-01-28 00:00:00

abstract：:Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of Plasmodium falciparum, the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, s...

journal_title：ACS medicinal chemistry letters

authors： Daub ME,Prudhomme J,Ben Mamoun C,Le Roch KG,Vanderwal CD

更新日期：2017-02-16 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：: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 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：:With only two new classes of antibiotics developed in the last 40 years, novel antibiotics are desperately needed to combat the growing problem of multidrug-resistant and extensively drug resistant bacteria, particularly Gram-negative bacteria. Described in this letter is the synthesis and antibiotic activity of 1,2,4...

journal_title：ACS medicinal chemistry letters

authors： Huggins WM,Minrovic BM,Corey BW,Jacobs AC,Melander RJ,Sommer RD,Zurawski DV,Melander C

更新日期：2016-11-12 00:00:00

abstract：:A new series of potent TG2 inhibitors are reported that employ a 4-aminopiperidine core bearing an acrylamide warhead. We establish the structure-activity relationship of this new series and report on the transglutaminase selectivity and in vitro ADME properties of selected compounds. We demonstrate that the compounds...

journal_title：ACS medicinal chemistry letters

authors： Prime ME,Brookfield FA,Courtney SM,Gaines S,Marston RW,Ichihara O,Li M,Vaidya D,Williams H,Pedret-Dunn A,Reed L,Schaertl S,Toledo-Sherman L,Beconi M,Macdonald D,Muñoz-Sanjuan I,Dominguez C,Wityak J

更新日期：2012-08-09 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 BRPF (bromodomain and PHD finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Here, we report the discovery, binding mode, and structure-activity relationship (SAR) of the first potent, selective series of inhibitors of the BRPF1 bromodomai...

journal_title：ACS medicinal chemistry letters

authors： Demont EH,Bamborough P,Chung CW,Craggs PD,Fallon D,Gordon LJ,Grandi P,Hobbs CI,Hussain J,Jones EJ,Le Gall A,Michon AM,Mitchell DJ,Prinjha RK,Roberts AD,Sheppard RJ,Watson RJ

更新日期：2014-09-10 00:00:00

abstract：:[(11)C]N-Methyl lansoprazole ([(11)C]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomography (PET) imaging. [(11)C]NML was synthesized from commercially available lansoprazole in 4.6% radiochemical yield (noncorrected RCY...

journal_title：ACS medicinal chemistry letters

authors： Shao X,Carpenter GM,Desmond TJ,Sherman P,Quesada CA,Fawaz M,Brooks AF,Kilbourn MR,Albin RL,Frey KA,Scott PJ

更新日期：2012-09-25 00:00:00

abstract：:Thirty-two diverse compounds were evaluated for their ability to inhibit both Pgp-mediated efflux in mouse T-lymphoma L5178 MDR1 and NorA-mediated efflux in S. aureus SA-1199B. Only four compounds were strong inhibitors of both efflux pumps. Three compounds were found to inhibit Pgp exclusively and strongly, while sev...

journal_title：ACS medicinal chemistry letters

authors： Brincat JP,Broccatelli F,Sabatini S,Frosini M,Neri A,Kaatz GW,Cruciani G,Carosati E

更新日期：2012-01-23 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：: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：: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：: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：:In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4'-methoxy- and 4'-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these ...

journal_title：ACS medicinal chemistry letters

authors： Zheng Z,Groaz E,Snoeck R,De Jonghe S,Herdewijn P,Andrei G

更新日期：2020-12-09 00:00:00

abstract：:Substitution of rigidified A3 adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in p...

journal_title：ACS medicinal chemistry letters

authors： Tosh DK,Crane S,Chen Z,Paoletta S,Gao ZG,Gizewski E,Auchampach JA,Salvemini D,Jacobson KA

更新日期：2015-05-20 00:00:00

abstract：:Tak-242 (resatorvid), a Toll-like Receptor 4 (TLR4) inhibitor, has been identified as a potent suppressor of innate inflammation. As a strategy to target Tak-242 to select tissue, four TLR4-inactive prodrugs were synthesized for activation via two different release mechanisms. Two nitrobenzyl Tak-242 prodrugs released...

journal_title：ACS medicinal chemistry letters

authors： Plunk MA,Alaniz A,Olademehin OP,Ellington TL,Shuford KL,Kane RR

更新日期：2020-01-03 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：:Derivatization efforts were continued to discover backups for a potent selective PPARγ modulator, DS-6930. In this Letter, the replacement of 2-pyridine ring in DS-6930 with 3- or 4-pyridyl group is reported. As the introduction of substituents on the pyridine ring did not provide potent partial agonists, modification...

journal_title：ACS medicinal chemistry letters

authors： Shinozuka T,Tsukada T,Fujii K,Tokumaru E,Matsui Y,Wakimoto S,Ogata T,Araki K,Sawamura R,Watanabe N,Mori M,Tanaka J

更新日期：2019-02-26 00:00:00

abstract：:The renal outer medullary potassium channel (ROMK or Kir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a p...

journal_title：ACS medicinal chemistry letters

authors： Tang H,Walsh SP,Yan Y,de Jesus RK,Shahripour A,Teumelsan N,Zhu Y,Ha S,Owens KA,Thomas-Fowlkes BS,Felix JP,Liu J,Kohler M,Priest BT,Bailey T,Brochu R,Alonso-Galicia M,Kaczorowski GJ,Roy S,Yang L,Mills SG,Garcia M

更新日期：2012-03-28 00:00:00

abstract：:A novel peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist 5c was developed with an EC50 of 8 nM for PPARα, 5 nM for PPARδ, and >300-fold selectivity against PPARγ (EC50 = 2939 nM), respectively. Further ADME and pharmacokinetic studies indicated 5c possessed distinguished in vitro and in vivo profiles...

journal_title：ACS medicinal chemistry letters

authors： Jiang Z,Liu X,Yuan Z,He H,Wang J,Zhang X,Gong Z,Hou L,Shen L,Guo F,Zhang J,Wang J,Xu D,Liu Z,Li H,Chen X,Long C,Li J,Chen S

更新日期：2019-06-24 00:00:00

abstract：:A new class of 4-aminoquinolines was synthesized and evaluated in vitro for antiplasmodial activity against both the chloroquine-sensitive (3D7) and -resistant (K1 and W2) strains. The most active compounds 3c-3e had acceptable cytotoxicity but showed strong inhibition toward a panel of cytochrome P450 enzymes in vitr...

journal_title：ACS medicinal chemistry letters

authors： Tukulula M,Njoroge M,Abay ET,Mugumbate GC,Wiesner L,Taylor D,Gibhard L,Norman J,Swart KJ,Gut J,Rosenthal PJ,Barteau S,Streckfuss J,Kameni-Tcheudji J,Chibale K

更新日期：2013-10-01 00:00:00