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Journal of Medicinal Chemistry

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https://www.readbyqxmd.com/read/28324649/sulfonamides-as-selective-nav1-7-inhibitors-optimizing-potency-pharmacokinetics-and-metabolic-properties-to-obtain-atropisomeric-quinolinone-am-0466-that-affords-robust-in-vivo-activity
#1
Russell F Graceffa, Alessandro A Boezio, Jessica Able, Steven Altmann, Loren M Berry, Christiane M Boezio, John R Butler, Margaret Y Chu-Moyer, Melanie Cooke, Erin F DiMauro, Thomas A Dineen, Elma Feric Bojic, Robert S Foti, Robert T Fremeau, Angel Guzman-Perez, Hua Gao, Hakan Gunaydin, Hongbing Huang, Liyue Huang, Christopher Ilch, Michael Jarosh, Thomas Kornecook, Charles R Kreiman, Daniel S La, Joseph Ligutti, Benjamin Charles Milgram, Min-Hwa Jasmine Lin, Isaac E Marx, Hanh Nho Nguyen, Emily A Peterson, Gwen Rescourio, John Roberts, Laurie B Schenkel, Roman Shimanovich, Brian Andrew Sparling, John Stellwagen, Kristin Taborn, Karina R Vaida, Jean Wang, John T S Yeoman, Violeta L Yu, Dawn Zhu, Bryan D Moyer, Matthew M Weiss
Due to its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a novel series of atropisomeric quinolinone sulfonamide inhibitors of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms...
March 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28323427/kinetin-riboside-and-its-protides-activate-the-parkinson-s-disease-associated-pten-induced-putative-kinase-1-pink1-independent-of-mitochondrial-depolarisation
#2
Laura Osgerby, Yu-Chiang Lai, Peter J Thornton, Joseph Amalfitano, Cécile S Le Duff, Iqra Jabeen, Hachemi Kadri, Ageo Miccoli, James H R Tucker, Miratul M K Muqit, Youcef Mehellou
Since loss of function mutations of PINK1 lead to early-onset Parkinson's disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases...
March 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28323425/structure-based-design-of-highly-selective-and-potent-g-protein-coupled-receptor-kinase-2-inhibitors-based-on-paroxetine
#3
Helen V Waldschmidt, Kristoff T Homan, Marilyn C Cato, Osvaldo Cruz-Rodríguez, Alessandro Cannavo, Michael W Wilson, Jianliang Song, Joseph Y Cheung, Walter J Koch, John J G Tesmer, Scott D Larsen
In heart failure, the β-adrenergic receptors (βARs) become desensitized and uncoupled from heterotrimeric G proteins. This process is initiated by G protein-coupled receptor kinases (GRKs), some of which are upregulated in the failing heart making them desirable therapeutic targets. The selective serotonin reuptake inhibitor, paroxetine, was previously identified as a GRK2 inhibitor. Utilizing a structure based drug design approach we modified paroxetine to generate a small compound library. Included in this series is a highly potent and selective GRK2 inhibitor, 14as, with an IC50 of 30 nM against GRK2 and greater than 230-fold selectivity over other GRKs and kinases...
March 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28277663/development-of-fluorinated-analogues-of-perhexiline-with-improved-pharmacokinetic-properties-and-retained-efficacy
#4
Chih-Chung Tseng, Hannah Noordali, Monica Sani, Melanie Madhani, Denis M Grant, Michael P Frenneaux, Matteo Zanda, Iain R Greig
We designed and synthesized perhexiline analogues that have the same therapeutic profile as the parent cardiovascular drug but lacking its metabolic liability associated with CYP2D6 metabolism. Cycloalkyl perhexiline analogues 6a-j were found to be unsuitable for further development, as they retained a pharmacokinetic profile very similar to that shown by the parent compound. Multistep synthesis of perhexiline analogues incorporating fluorine atoms onto the cyclohexyl ring(s) provided a range of different fluoroperhexiline analogues...
March 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28257574/17%C3%AE-hydroxywithanolides-as-sensitizers-of-renal-carcinoma-cells-to-tumor-necrosis-factor-%C3%AE-related-apoptosis-inducing-ligand-trail-mediated-apoptosis-structure-activity-relationships
#5
Ya-Ming Xu, Alan D Brooks, E M Kithsiri Wijeratne, Curtis J Henrich, Poonam Tewary, Thomas J Sayers, A A Leslie Gunatilaka
Renal cell carcinoma (RCC) is a cancer with poor prognosis, and the 5-year survival rate of patients with metastatic RCC is 5-10%. Consequently, treatment of metastatic RCC represents an unmet clinical need. Screening of a 50 000-member library of natural and synthetic compounds for sensitizers of RCC cells to TRAIL-mediated apoptosis led to identification of the 17β-hydroxywithanolide (17-BHW), withanolide E (1), as a promising lead. To explore structure-activity relationships, we obtained natural and semisynthetic withanolides 1, 2a, 2c, and 3-36 and compared their ability to sensitize TRAIL-mediated apoptosis in a panel of renal carcinoma cells...
March 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28319392/scaffold-repurposing-of-nucleosides-adenosine-receptor-agonists-enhanced-activity-at-the-human-dopamine-and-norepinephrine-sodium-symporters
#6
Dilip K Tosh, Aaron Janowsky, Amy J Eshleman, Eugene Warnick, Zhan-Guo Gao, Zhoumou Chen, Elizabeth Gizewski, John A Auchampach, Daniela Salvemini, Kenneth A Jacobson
We have repurposed (N)-methanocarba adenosine derivatives (A3 adenosine receptor (AR) agonists) to enhance radioligand binding allosterically at the human dopamine (DA) transporter (DAT) and inhibit DA uptake. We extended the structure-activity relationship of this series with small N(6)-alkyl substitution, 5'-esters, deaza modifications of adenine, and ribose restored in place of methanocarba. C2-(5-Halothien-2-yl)-ethynyl 5'-methyl 9 (MRS7292) and 5'-ethyl 10 (MRS7232) esters enhanced binding at DAT (EC50 ∼ 35 nM) and at the norepinephrine transporter (NET)...
March 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28272894/1-4-substituted-triazoles-as-nonsteroidal-anti-androgens-for-prostate-cancer-treatment
#7
Claudia Ferroni, Antonella Pepe, Yeong Sang Kim, Sunmin Lee, Andrea Guerrini, Marco Daniele Parenti, Anna Tesei, Alice Zamagni, Michela Cortesi, Nadia Zaffaroni, Michelandrea De Cesare, Giovanni Luca Beretta, Jane B Trepel, Sanjay V Malhotra, Greta Varchi
Prostate cancer (PC) is the fifth leading cause of cancer death in men, and the androgen receptor (AR) represents the primary target for PC treatment, even though the disease frequently progresses toward androgen-independent forms. Most of the commercially available nonsteroidal antiandrogens show a common scaffold consisting of two aromatic rings connected by a linear or a cyclic spacer. By taking advantage of a facile, one-pot click chemistry reaction, we report herein the preparation of a small library of novel 1,4-substituted triazoles with AR antagonistic activity...
March 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28306255/development-of-potent-and-selective-antagonists-for-the-utp-activated-p2y4-receptor
#8
Muhammad Rafehi, Enas Malik, Alexander Neumann, Aliaa Abdelrahman, Theodor Hanck, Vigneshwaran Namasivayam, Christa E Müller, Younis Baqi
P2Y4 is a Gq protein-coupled receptor activated by uridine-5'-triphosphate (UTP), which is widely expressed in the body, e.g., in intestine, heart, and brain. No selective P2Y4 receptor antagonist has been described so far. Therefore, we developed and optimized P2Y4 antagonists based on an anthraquinone scaffold. Potency was assessed by a fluorescence-based assay measuring inhibition of UTP-induced intracellular calcium release in 1321N1 astrocytoma cells stably transfected with the human P2Y4 receptor. The most potent compound of the present series, sodium 1-amino-4-[4-(2,4-dimethylphenylthio)phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (PSB-16133, 61) exhibited an IC50 value of 233 nM, selectivity versus other P2Y receptor subtypes, and is thought to act as an allosteric antagonist...
March 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28304162/rational-design-synthesis-and-biological-evaluation-of-heterocyclic-quinolones-targeting-the-respiratory-chain-of-mycobacterium-tuberculosis
#9
Weiqian David Hong, Peter D Gibbons, Suet C Leung, Richard Amewu, Paul A Stocks, Andrew Valentine Stachulski, Pedro C Horta, Maria Lurdes Santos Cristiano, Alison E Shone, Darren Moss, Alison Ardrey, Raman Sharma, Ashley J Warman, Paul T P Bedingfield, Nicholas E Fisher, Ghaith Aljayyoussi, Sally Mead, Maxine Caws, Neil G Berry, Stephen A Ward, Giancarlo A Biagini, Paul M O'Neill, Gemma Louise Nixon
A High-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). 11,000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11,000 compounds) and in-house screening of a limited number of quinolones (50 compounds) identified ~100 hits and four distinct chemotypes, the most promising of which contained the quinolone core...
March 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28277660/discovery-of-potent-and-orally-bioavailable-gpr40-full-agonists-bearing-thiophen-2-ylpropanoic-acid-scaffold
#10
He Li, Qi Huang, Cheng Chen, Bin Xu, He-Yao Wang, Ya-Qiu Long
The free fatty acid receptor GPR40 is predominantly expressed in pancreatic β-cells and enhances insulin secretion in a glucose dependent manner. Therefore, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia for the treatment of type 2 diabetes mellitus (T2DM). Chemically and structurally diverse GPR40 agonists with high safety are pursued for the clinical development of GPR40-based pharmacotherapeutics. Herein we report our design and discovery of a new chemotype of GPR40 agonists free of the typical phenylpropanoic acid scaffold...
March 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28272885/lead-development-of-thiazolylsulfonamides-with-carbonic-anhydrase-inhibitory-action
#11
Fabrizio Carta, Alexander Birkmann, Tamara Pfaff, Helmut Buschmann, Wilfried Schwab, Holger Zimmermann, Alfonso Maresca, Claudiu T Supuran
A series of congeners structurally related to pritelivir, N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, a helicase-primase inhibitor for the treatment of herpes simplex virus infections, was prepared. The synthesized primary and secondary sulfonamides were investigated as inhibitors of six physiologically and pharmacologically relevant human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, the cytosolic enzymes hCA I and II, the mitochondrial ones hCA VA and VB, and the transmembrane, tumor associated hCA IX and XII...
March 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28301155/exploration-of-2-pyridin-4-ylmethyl-amino-nicotinamide-derivatives-as-potent-reversal-agents-against-p-glycoprotein-mediated-multidrug-resistance
#12
Qianqian Qiu, Wei Shi, Zheng Li, Bo Zhang, Miaobo Pan, Jian Cui, Yuxuan Dai, Wenlong Huang, Hai Qian
Overexpression of the ATP-binding cassette (ABC) transport proteins, like ABCB1, commonly referred to as P-glycoprotein (P-gp), initiates active efflux of a broad spectrum of unrelated chemotherapeutic drugs in structure and function, leading to chemotherapy failure. A series of 2-((pyridin-4-ylmethyl)amino)nicotinamide derivatives as potent reversal agents against P-glycoprotein-mediated multidrug resistance (MDR) were designed and synthesized. The majority of target compounds displayed great reversal potency, especially 9n...
March 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28301142/manganese-complex-of-ethylenediaminetetra-acetic-acid-edta-benzothiazole-aniline-bta-conjugate-as-a-potential-liver-targeting-mri-contrast-agent
#13
Md Kamrul Islam, Soyeon Kim, Hee-Kyung Kim, Subin Park, Gang Ho Lee, Hyo Jeung Kang, Jae Chang Jung, Joon-Suk Park, Tae-Jeong Kim, Yongmin Chang
A novel manganese (II) complex based on an ethylenediaminetetraacetic acid (EDTA) coordination cage bearing a benzothiazole aniline (BTA) moiety (Mn-EDTA-BTA) was designed and synthesized for use as a liver-specific MRI contrast agent with high chelation stability. In addition to forming a hydrophilic, stable complex with Mn2+, this new Mn chelate was rapidly taken up by liver hepatocytes and excreted by the kidneys and biliary system. The kinetic inertness and R1 relaxivity of the complex were much higher than those of mangafodipir trisodium (MnDPDP), a clinically approved liver-specific MRI contrast agent...
March 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28300404/structural-basis-of-small-molecule-aggregate-induced-inhibition-of-a-protein-protein-interaction
#14
Jonathan M Blevitt, Michael D Hack, Krystal L Herman, Paul F Jackson, Paul J Krawczuk, Alec D Lebsack, Annie X Liu, Taraneh Mirzadegan, Marina I Nelen, Aaron N Patrick, Stefan Steinbacher, Marcos E Milla, Kevin J Lumb
A prevalent observation in high-throughput screening and drug discovery programs is the inhibition of protein function by small-molecule compound aggregation. Here, we present the X-ray structural description of aggregation-based inhibition of a protein-protein interaction involving tumor necrosis factor α (TNFα). An ordered conglomerate of an aggregating small-molecule inhibitor (JNJ525) induces a quaternary structure switch of TNFα that inhibits the protein-protein interaction between TNFα and TNFα receptors...
March 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28300398/novel-bivalent-ligands-based-on-the-sumanirole-pharmacophore-reveal-dopamine-d2-receptor-d2r-biased-agonism
#15
Alessandro Bonifazi, Hideaki Yano, Michael P Ellenberger, Ludovic Muller, Vivek Kumar, Mu-Fa Zou, Ning Sheng Cai, Adrian M Guerrero, Amina S Woods, Lei Shi, Amy Hauck Newman
The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by Gi/o-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment...
March 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28266845/synthesis-antiviral-potency-in-vitro-admet-and-x-ray-structure-of-potent-cd4-mimics-as-entry-inhibitors-that-target-the-phe43-cavity-of-hiv-1-gp120
#16
Francesca Curreli, Young Do Kwon, Dmitry S Belov, Ranjith R Ramesh, Alexander V Kurkin, Andrea Altieri, Peter D Kwong, Asim K Debnath
In our attempt to optimize the lead HIV-1 entry antagonist, NBD-11021, we present in this study the rational design and synthesis of 60 new analogues and determination of their antiviral activity in a single-cycle and a multicycle infection assay to derive a comprehensive structure-activity relationship (SAR). Two of these compounds, NBD-14088 and NBD-14107, showed significant improvement in antiviral activity compared to the lead entry antagonist in a single-cycle assay against a large panel of Env-pseudotyped viruses...
March 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28296398/discovery-of-an-acrylic-acid-based-tetrahydroisoquinoline-as-an-orally-bioavailable-selective-estrogen-receptor-degrader-for-er%C3%AE-breast-cancer
#17
Heather E Burks, Tinya Abrams, Christina A Kirby, Jason Baird, Alexander Fekete, Lawrence G Hamann, Sunkyu Kim, Franco Lombardo, Alice Loo, Danuta Lubicka, Kaitlin Macchi, Donald P McDonnell, Yuji Mishina, John D Norris, Jill Nunez, Chitra Saran, Yingchuan Sun, Noel M Thomsen, Chunrong Wang, Jianling Wang, Stefan Peukert
Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.
March 15, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28296396/seeking-the-elusive-long-acting-ozonide-discovery-of-artefenomel-oz439
#18
Ho Shin Kim, Jared T Hammill, R Kiplin Guy
The majority of frontline therapies for the treatment of malaria are combination drugs containing artemisinin (or its semisynthetic analogs), known as artemisinin combination therapies (ACTs). While generally efficacious, ACTs and the first generation fully synthetic ozonide, arterolane (OZ277, 1), suffer from rapid clearance requiring 3-day dosing regimens. Extensive structure-activity studies led to the discovery of a second-generation ozonide, artefenomel (OZ439, 2), which has overcome this limitation, maintaining the rapid onset of action and potent activity of the artemisinin derivatives while exhibiting greatly improved pharmacokinetics, low projected cost of goods, prophylactic activity, and the potential for a single dose cure...
March 15, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28245116/discovery-of-an-orally-selective-inhibitor-of-signal-transducer-and-activator-of-transcription-3-using-advanced-multiple-ligand-simultaneous-docking
#19
Wenying Yu, Chenglong Li, Wenda Zhang, Yuanzheng Xia, Shanshan Li, Jia-Yuh Lin, Keqin Yu, Mu Liu, Lei Yang, Jianguang Luo, Yijun Chen, Hongbin Sun, Lingyi Kong
Targeting signal transducer and activator of transcription 3 (STAT3) is a potential anticancer strategy. However, STAT3 inhibitors with good selectivity and bioavailability are rare. The aim of this study was to discover selective direct STAT3 inhibitors with good druglikeness. By the advanced multiple ligand simultaneous docking (AMLSD) method, compound 9 was designed as an orally bioavailable STAT3 inhibitor that presented superior druggability and selectivity compared with other representative STAT3 inhibitors...
March 15, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28230985/discovery-of-competitive-and-noncompetitive-ligands-of-the-organic-cation-transporter-1-oct1-slc22a1
#20
Eugene C Chen, Natalia Khuri, Xiaomin Liang, Adrian Stecula, Huan-Chieh Chien, Sook Wah Yee, Yong Huang, Andrej Sali, Kathleen M Giacomini
Organic cation transporter 1 (OCT1) plays a critical role in the hepatocellular uptake of structurally diverse endogenous compounds and xenobiotics. Here we identified competitive and noncompetitive OCT1-interacting ligands in a library of 1780 prescription drugs by combining in silico and in vitro methods. Ligands were predicted by docking against a comparative model based on a eukaryotic homologue. In parallel, high-throughput screening (HTS) was conducted using the fluorescent probe substrate ASP(+) in cells overexpressing human OCT1...
March 15, 2017: Journal of Medicinal Chemistry
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