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ACS Medicinal Chemistry Letters

Sumanta Garai, Krishnamohan S Raja, Roger L Papke, Jeffrey R Deschamps, M Imad Damaj, Ganesh A Thakur
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 crystallography studies revealed its absolute " S " stereochemistry. B-973B was effective in attenuating pain behavior and decreasing paw edema (formalin test), and its analgesic effects were mediated through α7 nAChR...
November 8, 2018: ACS Medicinal Chemistry Letters
Allen F Brooks, Lindsey R Drake, Xia Shao, Austin Zhao, Peter J H Scott, Michael R Kilbourn
The development of a positron emission tomography (PET)/magnetic resonance spectroscopy (MRS) hybrid imaging agent allows for functional imaging by both methods with a single imaging agent. Enzyme substrates that are cleaved to form two metabolites present an interesting opportunity, as the unique metabolites generated might each be detected by a different modality. To be successful, such enzyme substrates would require administration of doses that (a) reach the in vivo target tissue at concentrations necessary for MRS imaging, (b) do not show substrate inhibition of tissue uptake or enzymatic activity, and (c) provide PET images that still reflect the action of the enzyme...
November 8, 2018: ACS Medicinal Chemistry Letters
Gaurav K Ganotra, Rebecca C Wade
A growing consensus is emerging that optimizing the drug-target affinity alone under equilibrium conditions does not necessarily translate into higher potency in vivo and that instead binding kinetic parameters should be optimized to ensure better efficacy. Therefore, in silico methods are needed to predict the kinetic parameters and the mechanistic determinants of drug-protein binding. Here we demonstrate the application of COMparative BINding Energy (COMBINE) analysis to derive quantitative structure-kinetics relationships (QSKRs) for the dissociation rate constants ( k off ) of inhibitors of heat shock protein 90 (HSP90) and HIV-1 protease...
November 8, 2018: ACS Medicinal Chemistry Letters
Tony Fröhlich, Anita Kiss, János Wölfling, Erzsébet Mernyák, Ágnes E Kulmány, Renáta Minorics, István Zupkó, Maria Leidenberger, Oliver Friedrich, Barbara Kappes, Friedrich Hahn, Manfred Marschall, Gyula Schneider, Svetlana B Tsogoeva
Artemisinin-estrogen hybrids were for the first time both synthesized and investigated for their in vitro biological activity against malaria parasites ( Plasmodium falciparum 3D7), human cytomegalovirus (HCMV), and a panel of human malignant cells of gynecological origin containing breast (MCF7, MDA-MB-231, MDA-MB-361, T47D) and cervical tumor cell lines (HeLa, SiHa, C33A). In terms of antimalarial efficacy, hybrid 8 (EC50 = 3.8 nM) was about two times more active than its parent compound artesunic acid ( 7 ) (EC50 = 8...
November 8, 2018: ACS Medicinal Chemistry Letters
Xiaoyun Lu, Tao Zhang, Su-Jie Zhu, Qiuju Xun, Lingjiang Tong, Xianglong Hu, Yan Li, Shingpan Chan, Yi Su, Yiming Sun, Yi Chen, Jian Ding, Cai-Hong Yun, Hua Xie, Ke Ding
EGFRC797S mutation inducing resistance against third generation EGFR inhibitor drugs is an emerging "unmet clinical need" for nonsmall cell lung cancer patients. The pyrimidopyrimidinone derivative JND3229 was identified as a new highly potent EGFRC797S inhibitor with single digit nM potency. It also exhibited good in vitro and in vivo monodrug anticancer efficacy in a xenograft mouse model of BaF3/EGFR19D/T790M/C797S cells. A high-resolution X-ray crystallographic structure was also determined to elucidate the interactions between JND3229 and EGFRT790M/C797S ...
November 8, 2018: ACS Medicinal Chemistry Letters
Yong Zhang, Yufen Zhao, Andrew J Tebben, Steven Sheriff, Max Ruzanov, Mark P Fereshteh, Yi Fan, Jonathan Lippy, Jesse Swanson, Ching-Ping Ho, Barri S Wautlet, Anne Rose, Karen Parrish, Zheng Yang, Andrew F Donnell, Liping Zhang, Brian E Fink, Gregory D Vite, Karen Augustine-Rauch, Joseph Fargnoli, Robert M Borzilleri
The multifunctional cytokine TGFβ plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGFβ signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFβ receptor kinase inhibitors with excellent selectivity for TGFβ receptor 1 kinase. The combination of compound 3f and an antimouse-PD-1 antibody demonstrated significantly improved antitumor efficacy compared to either treatment alone in a murine tumor model...
November 8, 2018: ACS Medicinal Chemistry Letters
Yanmei Hu, Raymond Kin Hau, Yuanxiang Wang, Peter Tuohy, Yongtao Zhang, Shuting Xu, Chunlong Ma, Jun Wang
Majority of current circulating influenza A viruses carry the S31N mutation in their M2 genes, rendering AM2-S31N as a high profile antiviral drug target. With our continuous interest in developing AM2-S31N channel blockers as novel antivirals targeting both oseltamivir-sensitive and -resistant influenza A viruses, we report herein the structure-property relationship studies of AM2-S31N inhibitors. The goal was to identify lead compounds with improved microsomal stability and membrane permeability. Two lead compounds, 10d and 10e , were found to have high mouse and human liver microsomal stability ( T 1/2 > 145 min) and membrane permeability (>200 nm/s)...
November 8, 2018: ACS Medicinal Chemistry Letters
Lian-Fang Yang, Yajing Xing, Jie-Xin Xiao, Jia Xie, Wei Gao, Jiuqing Xie, Li-Ting Wang, Jinhua Wang, Mingyao Liu, Zhengfang Yi, Wen-Wei Qiu
Bmi-1 is overexpressed in colorectal cancer (CRC) and served as a novel therapeutic target for the treatment of CRC. A series of novel cyanoenone-modified diterpenoid analogs was synthesized and investigated for their antiproliferative activity against CRC cells. The results showed that most of these compounds exhibited potent antiproliferative and Bmi-1 inhibitory activity. Among them, the most active compound 33 ( SH498 ) showed more potent antiproliferative activity than the positive control compound PTC-209...
November 8, 2018: ACS Medicinal Chemistry Letters
Ryo Nakajima, Zora Nováková, Werner Tueckmantel, Lucia Motlová, Cyril Bařinka, Alan P Kozikowski
The design and synthesis of prostate specific membrane antigen (PSMA) ligands derived from 2-aminoadipic acid, a building block that has not previously been used to construct PSMA ligands, are reported. The effects of both the linker length and of an N-substituent of our PSMA ligands were probed, and X-ray structures of five of these ligands bound to PSMA were obtained. Among the ligands disclosed herein, 13b showed the highest inhibitory activity for PSMA. As ligand 13b can readily be radiolabeled since its fluorine atom is adjacent to the nitrogen atom of its pyridine ring, the use of this and related compounds as theranostics can be pursued...
November 8, 2018: ACS Medicinal Chemistry Letters
Francesca Cantini, Vito Calderone, Lorenzo Di Cesare Mannelli, Magdalena Korsak, Leonardo Gonnelli, Oscar Francesconi, Carla Ghelardini, Lucia Banci, Cristina Nativi
The formation of amorphous protein aggregates containing human superoxide dismutase (hSOD1) is thought to be involved in amyotrophic lateral sclerosis onset. cis -Platin inhibits the oligomerization of apo hSOD1, but its toxicity precludes any possible use in therapy. Herein, we propose a less toxic platinum complex, namely oxa/ cis -platin, as hSOD1 antiaggregation lead compound. Oxa/ cis -platin is able to interact with hSOD1 in the disulfide oxidized apo form by binding cysteine 111 (Cys111). The mild neurotoxic phenomena induced in vitro and in vivo by oxa/ cis -platin can be successfully reverted by using lypoyl derivatives, which do not interfere with the antiaggregation properties of the platin derivative...
November 8, 2018: ACS Medicinal Chemistry Letters
Weiguo Liu, Zahid Hussain, Yi Zang, Ramzi F Sweis, F Anthony Romero, Paul E Finke, Remond Moningka, Jianming Bao, Michael A Plotkin, Jin Shang, Karen H Dingley, Gino Salituro, Beth Ann Murphy, Andrew D Howard, Feroze Ujjainwalla, Harold B Wood, Joseph L Duffy
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 profiles compared to those of the original lead compound 1 while maintaining pharmacodynamic efficacy. The optimized cyclopropyl analogue 13 demonstrated efficacy in a mouse oral glucose tolerance test and an improved metabolic profile and pharmacokinetic properties in rhesus monkey studies...
November 8, 2018: ACS Medicinal Chemistry Letters
Weiguo Liu, Pengcheng P Shao, Gui-Bai Liang, John Bawiec, Jiafang He, Susan D Aster, Margaret Wu, Garry Chicchi, John Wang, Kwei-Lan Tsao, Jin Shang, Gino Salituro, Yun-Ping Zhou, Cai Li, Taro E Akiyama, Daniel E Metzger, Beth Ann Murphy, Andrew D Howard, Ann E Weber, Joseph L Duffy
We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal off-target activities as compared to previously reported compounds. Starting from the reported SSTR5 antagonist 1 , we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10 emerged as a new highly potent and selective SSTR5 antagonist. Compound 10 lowered glucose excursion by 94% in an oral glucose tolerance test (OGTT) in mice following a 3 mg/kg oral dose...
November 8, 2018: ACS Medicinal Chemistry Letters
Matthew G LaPorte, James C Burnett, Raffaele Colombo, Stacie L Bulfer, Celeste Alverez, Tsui-Fen Chou, R Jeffrey Neitz, Neal Green, William J Moore, Zhizhou Yue, Shan Li, Michelle R Arkin, Peter Wipf, Donna M Huryn
Optimization of the side-chain of a phenyl indole scaffold identified from a high-throughput screening campaign for inhibitors of the AAA+ ATPase p97 is reported. The addition of an N -alkyl piperazine led to high potency of this series in a biochemical assay, activity in cell-based assays, and excellent pharmaceutical properties. Molecular modeling based on a subsequently obtained cryo-EM structure of p97 in complex with a phenyl indole was used to rationalize the potency of these allosteric inhibitors.
November 8, 2018: ACS Medicinal Chemistry Letters
Robert B Kargbo
No abstract text is available yet for this article.
November 8, 2018: ACS Medicinal Chemistry Letters
Warren C Chan, Brian León, Kelsey A Krug, Ashay Patel, James J La Clair, Michael D Burkart
The spliceosome has been shown to be a promising target for the development of new anticancer therapeutics. Synthetic and chemical biological efforts directed toward the development of natural product-based splice modulators (SPLMs) have shown that the potency of these compounds derives from their ability to selectively affect the alternate splicing of apoptotic genes in tumor cells. However, questions remain regarding the mechanistic understanding of splice modulation as well as the selectivity with which SPLMs impact certain genes...
November 8, 2018: ACS Medicinal Chemistry Letters
Justin S Smith, Adrian E Roitberg, Olexandr Isayev
In this Viewpoint, we discuss the current progress in applications of machine learning (ML) and artificial intelligence (AI) to meet the challenges of computational drug discovery. We identify several areas where existing methods have the potential to accelerate pharmaceutical research and disrupt more traditional approaches.
November 8, 2018: ACS Medicinal Chemistry Letters
Hassan Al-Ali, Ginamarie Debevec, Radleigh G Santos, Richard A Houghten, Jennifer C Davis, Adel Nefzi, Vance P Lemmon, John L Bixby, Marc A Giulianotti
Central nervous system (CNS) neurons typically fail to regrow their axons after injury. Injuries or neuropathies that damage CNS axons and disrupt neuronal circuitry often result in permanent functional deficits. Axon regeneration is therefore an intensely pursued therapeutic strategy for numerous CNS disorders. Phenotypic screens utilizing primary neurons have proven successful at identifying agents that promote axon regeneration in vivo . Here, we report the screening of mixture-based combinatorial small molecule libraries in a phenotypic assay utilizing primary CNS neurons and the discovery of neurite outgrowth promoters with low nanomolar potency...
October 11, 2018: ACS Medicinal Chemistry Letters
Autumn R Flynn, Suzanne G Mays, Eric A Ortlund, Nathan T Jui
The orphan nuclear receptor Liver Receptor Homologue-1 (LRH-1) is an emerging drug target for metabolic disorders. The most effective known LRH-1 modulators are phospholipids or synthetic hexahydropentalene compounds. While both classes have micromolar efficacy, they target different portions of the ligand binding pocket and activate LRH-1 through different mechanisms. Guided by crystallographic data, we combined aspects of both ligand classes into a single scaffold, resulting in the most potent and efficacious LRH-1 agonists to date...
October 11, 2018: ACS Medicinal Chemistry Letters
Rita Meleddu, Simona Distinto, Filippo Cottiglia, Rossella Angius, Marco Gaspari, Domenico Taverna, Claudia Melis, Andrea Angeli, Giulia Bianco, Serenella Deplano, Benedetta Fois, Sonia Del Prete, Clemente Capasso, Stefano Alcaro, Francesco Ortuso, Matilde Yanez, Claudiu T Supuran, Elias Maccioni
A novel series of of 4-[(3-phenyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides ( EMAC10111a-g ) was synthesized and assayed toward both human carbonic anhydrase isozymes I, II, IX, and XII and cyclooxygenase isoforms. The majority of these derivatives preferentially inhibit hCA isoforms II and XII and hCOX-2 isozyme, indicating that 2,3,4-trisubstituted 2,3-dihydrothiazoles are a promising scaffold for the inhibition of hCA isozymes and of hCOX-2 enzyme. The nature of the substituent at the dihydrothiazole ring position 4 influenced the activity and selectivity toward both enzyme families...
October 11, 2018: ACS Medicinal Chemistry Letters
Pamela A Haile, Linda N Casillas, Michael J Bury, John F Mehlmann, Robert Singhaus, Adam K Charnley, Terry V Hughes, Michael P DeMartino, Gren Z Wang, Joseph J Romano, Xiaoyang Dong, Nikolay V Plotnikov, Ami S Lakdawala, Maire A Convery, Bartholomew J Votta, David B Lipshutz, Biva M Desai, Barbara Swift, Carol A Capriotti, Scott B Berger, Mukesh K Mahajan, Michael A Reilly, Elizabeth J Rivera, Helen H Sun, Rakesh Nagilla, Carol LePage, Michael T Ouellette, Rachel D Totoritis, Brian T Donovan, Barry S Brown, Khuram W Chaudhary, Peter J Gough, John Bertin, Robert W Marquis
RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog...
October 11, 2018: ACS Medicinal Chemistry Letters
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