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ACS Medicinal Chemistry Letters

Kyle Parcella, Kyle Eastman, Kap-Sun Yeung, Katharine A Grant-Young, Juliang Zhu, Tao Wang, Zhongxing Zhang, Zhiwei Yin, Dawn Parker, Kathy Mosure, Hua Fang, Ying-Kai Wang, Julie Lemm, Xiaoliang Zhuo, Umesh Hanumegowda, Mengping Liu, Karen Rigat, Maria Donoso, Maria Tuttle, Tatyana Zvyaga, Zuzana Haarhoff, Nicholas A Meanwell, Matthew G Soars, Susan B Roberts, John F Kadow
Iterative structure-activity analyses in a class of highly functionalized furo[2,3-b]pyridines led to the identification of the second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 (14), a potential clinical candidate. The key challenge of poor metabolic stability was overcome by strategic incorporation of deuterium at potential metabolic soft spots. The preclinical profile and status of BMT-052 (14) is described.
July 13, 2017: ACS Medicinal Chemistry Letters
Daniel G Silva, J Robert Gillespie, Ranae M Ranade, Zackary M Herbst, Uyen T T Nguyen, Frederick S Buckner, Carlos A Montanari, Michael H Gelb
The present work describes the synthesis of 22 new imidazopyridine analogues arising from medicinal chemistry optimization at different sites on the molecule. Seven and 12 compounds exhibited an in vitro EC50 ≤ 1 μM against Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei) parasites, respectively. Based on promising results of in vitro activity (EC50 < 100 nM), cytotoxicity, metabolic stability, protein binding, and pharmacokinetics (PK) properties, compound 20 was selected as a candidate for in vivo efficacy studies...
July 13, 2017: ACS Medicinal Chemistry Letters
Chen Jin, Shuai Wen, Qiumeng Zhang, Qiwen Zhu, Jiahui Yu, Wei Lu
Due to the low esterase activity in human plasma, many ester and carbonate prodrugs tested in humans may be less effective than that in preclinical animals. In this letter, PTX and SN-38 were attached to the N-1 position of 2-nitroimidazole via a carbonate linker. Presumably, 2-aminoimidazole may help promote the intramolecular hydrolysis of the carbonate bond. The prodrugs exhibited a considerable stability in buffers at different pH values as well as in human plasma. Furthermore, a rapid reduction was exhibited in the presence of nitroreductase...
July 13, 2017: ACS Medicinal Chemistry Letters
Carolina P Knubel, Constanza Insfran, Fernando F Martinez, Cintia Diaz Lujan, Ricardo E Fretes, Martin G Theumer, Laura Cervi, Claudia C Motran
The antiparasitic activity of 3-hydroxykynurenine (3-HK), one of the major tryptophan catabolites of the kynurenine pathway, against both Trypanosoma cruzi evolutive forms that are important for human infection, trypomastigotes (Tps) and amastigotes (Am), possible targets in the parasite and the drug toxicity to mammalian cells have been investigated. 3-HK showed a potent activity against Am with IC50 values in the micromolar concentration range, while the IC50 values to cause Tps death was ∼6000-times higher, indicating that the replicative form present in the vertebrate hosts is much more susceptible to 3-HK than bloodstream Tps...
July 13, 2017: ACS Medicinal Chemistry Letters
Kentaro Takayama, Cédric Rentier, Tomo Asari, Akari Nakamura, Yusuke Saga, Takahiro Shimada, Kei Nirasawa, Eri Sasaki, Kyohei Muguruma, Akihiro Taguchi, Atsuhiko Taniguchi, Yoichi Negishi, Yoshio Hayashi
Myostatin, a negative regulator of skeletal muscle growth, is a promising target for treating muscle atrophic disorders. Recently, we discovered a minimal myostatin inhibitor 1 (WRQNTRYSRIEAIKIQILSKLRL-amide) derived from positions 21-43 of the mouse myostatin prodomain. We previously identified key residues (N-terminal Trp(21), rodent-specific Tyr(27), and all aliphatic amino acids) required for effective inhibition through structure-activity relationship (SAR) studies based on 1 and characterized a 3-fold more potent inhibitor 2 bearing a 2-naphthyloxyacetyl group at position 21...
July 13, 2017: ACS Medicinal Chemistry Letters
Daniel C Elliott, John A Beutler, Kathlyn A Parker
The ring closing metathesis/transannular etherification approach to the englerin nucleus was adapted to provide two key intermediates for analogue synthesis: the 4-desmethyl Δ(5,6) tricycle and the 4-oxo Δ(5,6) tricycle. The former was elaborated to 4-desmethyl englerin A and the latter served as a common precursor for englerin A, 4-ethyl englerin A, and 4-isopropyl englerin A. 4-Desmethyl englerin A was less active than the natural product by an order of magnitude, but the 4-ethyl and 4-isopropyl analogues were comparable in activity to englerin A...
July 13, 2017: ACS Medicinal Chemistry Letters
Chad M Kormos, Pauline W Ondachi, Scott P Runyon, James B Thomas, S Wayne Mascarella, Ann M Decker, Hernán A Navarro, F Ivy Carroll
Potent and selective κ opioid receptor antagonists have been derived from the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of pure opioid receptor antagonists. In order to determine if the 3-hydroxyphenyl and/or the piperidine amino groups are required for obtaining the pure opioid antagonists, (3R)-7-hydroxy-N-[(1S)-2-methyl-1-(piperidine-1-ylmethyl)propyl]-1,2,3,4-tetrahydroiosquinoline-3-carboxamide (1), which does not have a 4-(3-hydroxyphenyl) group, and (3R)-N-(1R)-1-(cyclohexylmethyl)-2-methylpropyl]-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2), which does not have a 4-hydroxylphenyl or a piperidine amino group, were synthesized and evaluated for their [(35)S]GTPγS binding properties at the μ, δ, and κ opioid receptors...
July 13, 2017: ACS Medicinal Chemistry Letters
Terry D Crawford, James E Audia, Steve Bellon, Daniel J Burdick, Archana Bommi-Reddy, Alexandre Côté, Richard T Cummings, Martin Duplessis, E Megan Flynn, Michael Hewitt, Hon-Ren Huang, Hariharan Jayaram, Ying Jiang, Shivangi Joshi, James R Kiefer, Jeremy Murray, Christopher G Nasveschuk, Arianne Neiss, Eneida Pardo, F Anthony Romero, Peter Sandy, Robert J Sims, Yong Tang, Alexander M Taylor, Vickie Tsui, Jian Wang, Shumei Wang, Yongyun Wang, Zhaowu Xu, Laura Zawadzke, Xiaoqin Zhu, Brian K Albrecht, Steven R Magnuson, Andrea G Cochran
The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound...
July 13, 2017: ACS Medicinal Chemistry Letters
Satoshi Sogabe, Yusuke Kamada, Masanori Miwa, Ayumu Niida, Tomoya Sameshima, Masahiro Kamaura, Kazuko Yonemori, Shigekazu Sasaki, Jun-Ichi Sakamoto, Kotaro Sakamoto
The Ras proteins play roles in cell differentiation, proliferation, and survival. Aberrant signaling through Ras-mediated pathways in tumor cells occurs as a result of several types of mutational damage, which most frequently affects the amino acids G12, G13, and Q61. Recently, KRpep-2d was identified as a K-Ras(G12D) selective inhibitory peptide against the G12D mutant of K-Ras, which is a key member of the Ras protein family and an attractive cancer therapeutic target. In this study, the crystal structure of the human K-Ras(G12D) mutant was determined in complex with GDP and KRpep-2d at 1...
July 13, 2017: ACS Medicinal Chemistry Letters
Bernhard C Lechtenberg, Peter D Mace, E Hampton Sessions, Robert Williamson, Romain Stalder, Yann Wallez, Gregory P Roth, Stefan J Riedl, Elena B Pasquale
ERK is the effector kinase of the RAS-RAF-MEK-ERK signaling cascade, which promotes cell transformation and malignancy in many cancers and is thus a major drug target in oncology. Kinase inhibitors targeting RAF or MEK are already used for the treatment of certain cancers, such as melanoma. Although the initial response to these drugs can be dramatic, development of drug resistance is a major challenge, even with combination therapies targeting both RAF and MEK. Importantly, most resistance mechanisms still rely on activation of the downstream effector kinase ERK, making it a promising target for drug development efforts...
July 13, 2017: ACS Medicinal Chemistry Letters
Sukhen C Ghosh, Servando Hernandez Vargas, Melissa Rodriguez, Susanne Kossatz, Julie Voss, Kendra S Carmon, Thomas Reiner, Agnes Schonbrunn, Ali Azhdarinia
Fluorescently labeled imaging agents can identify surgical margins in real-time to help achieve complete resections and minimize the likelihood of local recurrence. However, photon attenuation limits fluorescence-based imaging to superficial lesions or lesions that are a few millimeters beneath the tissue surface. Contrast agents that are dual-labeled with a radionuclide and fluorescent dye can overcome this limitation and combine quantitative, whole-body nuclear imaging with intraoperative fluorescence imaging...
July 13, 2017: ACS Medicinal Chemistry Letters
Tomohiro Shirai, Kentaro Kumihashi, Mitsuyoshi Sakasai, Hiroshi Kusuoku, Yusuke Shibuya, Atsushi Ohuchi
The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary receptor for innocuous cold stimuli (<28 °C) in humans. TRPM8 agonists such as l-(-)-menthol are widely used as flavors and additives to impart briskness, in addition to medicinal uses for inflammation and pain. Though various natural and synthetic agonists have been explored, only few natural compounds are known. We report herein the identification and characterization of the novel neolignan agonist erythro- and threo-Δ(8')-7-ethoxy-4-hydroxy-3,3',5'-trimethoxy-8-O-4'-neolignan (1) with an EC50 of 0...
July 13, 2017: ACS Medicinal Chemistry Letters
Jonas Schartner, Andreas Nabers, Brian Budde, Julia Lange, Nina Hoeck, Jens Wiltfang, Carsten Kötting, Klaus Gerwert
Alzheimer's disease affects millions of human beings worldwide. The disease progression is characterized by the formation of plaques and neurofibrillary tangles in the brain, which are based on aggregation processes of the Aβ peptide and tau protein. Today there is no cure and even no in vitro assay available for the identification of drug candidates, which provides direct information concerning the protein secondary structure label-free. Therefore, we developed an attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) sensor, which uses surface bound antibodies to immobilize a desired target protein...
July 13, 2017: ACS Medicinal Chemistry Letters
Irawati K Kandela, Katherine J McAuliffe, Lauren E Cochran, Anthony G M Barrett, Brian M Hoffman, Andrew P Mazar, Evan R Trivedi
A series of porphyrazines (Pzs) with chiral bis-acetal moieties in the β-pyrrole positions ((2R,3R)-2,3-dimethyl-2,3-dimethoxy-1,4-diox-2-ene) have been synthesized and screened as antitumor agents in MDA-MB-231 breast tumor cells in vitro. The lead Pz 285 was further tested in a mouse tumor xenograft model with Td-tomato-luc2 fluorescent breast tumor cells (MDA-MB-231 LM24 Her2+) that are highly metastatic to the lungs. Pz 285 shows marked antitumor effects in vivo, with treated mice exhibiting longer median survival that we attribute to smaller primary tumor regrowth after resection and less occurrence of metastasis when compared to vehicle control groups...
July 13, 2017: ACS Medicinal Chemistry Letters
Corinne N Foley, Liang-An Chen, Dan L Sackett, James L Leighton
An approach to the validation of a linker strategy for the epothilone family of microtubule-stabilizing agents is reported. An analogue of epothilone B in which the C(6) methyl group has been replaced with a 4-azidobutyl group has been prepared by total chemical synthesis, and amides derived from the azido group have been shown to retain the activity of the parent compound. These results set the stage for an evaluation of the potential of the epothilones to serve as the drug component of antibody-drug conjugates and other selective tumor cell-targeting conjugates...
July 13, 2017: ACS Medicinal Chemistry Letters
Laura M Bohn, Jeffrey Aubé
The discovery and characterization of two classes of kappa opioid receptor agonists that are biased for G protein over βarrestin signaling are described.
July 13, 2017: ACS Medicinal Chemistry Letters
Hussain Dahodwala, Susan T Sharfstein
Biopharmaceutical sales were at $160 billion in 2016. With many top revenue biopharmaceuticals coming off patent in the next 4 years, there is a tremendous rush by leading biopharmaceutical companies worldwide to launch biosimilar versions of innovator products. However, these protein drugs are extremely difficult to copy. In this viewpoint, we will discuss the various drugs slated to lose patent protection and the challenges in manufacturing these drugs using current technologies. The Food and Drug Administration's regulatory role and definitions of similarity will be discussed, and finally, the scientific challenges in mimicking a protein drug in the current patent- and innovation-driven research field will be considered...
July 13, 2017: ACS Medicinal Chemistry Letters
Philip C Burcham
General levels of "pharmaceuticals literacy" are not high in contemporary societies. To address this educational need, in 2012 the University of Western Australia introduced an innovative multidisciplinary course for undergraduates within any degree program entitled PHAR1101: Drugs that Changed the World. Now ranking among the largest courses at the institution, PHAR1101 enrollments will likely approach 1000 students in 2017.
July 13, 2017: ACS Medicinal Chemistry Letters
Wenquan Yu, Ertong Li, Zhigang Lv, Ke Liu, Xiaohe Guo, Yuan Liu, Junbiao Chang
A novel 2',3'-dideoxy-2'-α-fluoro-2'-β-C-methyl-6-methoxy guanosine (8) and its phosphoramidate prodrug (1) have been designed and synthesized. Their biological activity was evaluated in both cytotoxicity and cell-based HCV replicon assays. Neither compounds exhibited cytotoxicity up to the highest concentration tested (100 μM) in the Huh-7 cell line. The prodrug (1) displayed nanomolar level antiviral activity (EC50 = 0.39-1.1 μM) against the HCV genotype (GT) 1a, 1b, 2a, and 1b S282T replicons.
June 8, 2017: ACS Medicinal Chemistry Letters
Hai-Yan Qian, Zhi-Long Wang, You-Lu Pan, Li-Li Chen, Xin Xie, Jian-Zhong Chen
Starting from a prototypical structure 1, we describe our efforts to design and obtain novel quinazoline/pyrimidine-2,4(1H,3H)-diones with high CB2 agonist potency and selectivity as well as improved physicochemical characteristics, mainly hydrophilicity. The most potent and selective CB2 agonists, 8 and 36, in this series were also endowed with lower logP values than that of GW842166X and lead compound 1. These derivatives appear to be promising lead compounds for the development of future CB2 agonists.
June 8, 2017: ACS Medicinal Chemistry Letters
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