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Bioorganic & Medicinal Chemistry Letters

Andrew S Felts, Katrina A Bollinger, Christopher J Brassard, Alice L Rodriguez, Ryan D Morrison, J Scott Daniels, Anna L Blobaum, Colleen M Niswender, Carrie K Jones, P Jeffrey Conn, Kyle A Emmitte, Craig W Lindsley
This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp3 character, uniform CYP450 -mediated metabolism across species, good functional potency and high CNS penetration...
November 10, 2018: Bioorganic & Medicinal Chemistry Letters
Manpreet Kaur, Palwinder Singh
Based on the molecular modelling studies, a rational modification of the lead molecule was made to develop highly potent compounds showing anti-cancer activity against human breast cancer cell lines MCF 7, MDA-MB-468 and T-47D. The most potent compounds have Log P and total polar surface area 4.4-5.4 and 59.8 Å, respectively and they also exhibited promising ADME profile.
November 10, 2018: Bioorganic & Medicinal Chemistry Letters
Nicholas Brotzman, Yiming Xu, Allison Graybill, Alexander Cocolas, Andrew Ressler, Navindra P Seeram, Hang Ma, Geneive E Henry
Carvacrol (1) and thymol (2) were converted to their alkyl 4-oxobutanoate derivatives (7-20) in three steps, and evaluated for tyrosinase inhibitory activity. The compounds showed structure-dependent activity, with all alkyl 4-oxobutanoates, except 7 and 20, showing better inhibitory activity than the precursor 4-oxobutanoic acids (5 and 6). In general, thymol derivatives exhibited a higher percent inhibitory activity than carvacrol derivatives at 500 μM. Derivatives containing three-carbon and four-carbon alkyl groups gave the strongest activity (carvacrol derivatives 9-12, IC50  = 128...
November 8, 2018: Bioorganic & Medicinal Chemistry Letters
Masanao Inagaki, Masaharu Kume, Yoshinori Tamura, Shinichiro Hara, Yoshihisa Goto, Nobuhiro Haga, Tsuyoshi Hasegawa, Takashi Nakamura, Katsumi Koike, Shuuichi Oonishi, Toshiyuki Kanemasa, Hiroyuki Kai
Structure-activity relationship studies of several morphinan derivatives were conducted to obtain dual antagonists for μ- and δ-opioid receptors. We discovered peripherally restricted dual antagonists for μ/δ-opioid receptors as a new chemotype with a morphinan scaffold, which are orally available and do not easily pass the blood-brain barrier. As we expected, some of these compounds inhibit opioid-induced constipation and emesis/vomiting with limited potential to interfere the analgesic effects of morphine...
November 7, 2018: Bioorganic & Medicinal Chemistry Letters
Hang-Hee Cho, Hyeon Soo Park, Sun-Hee Jang, Chungkil Won, Hong-Duck Kim, Tae Hoon Kim, Jae-Hyeon Cho
The purpose of this study was to investigate the mechanisms underlying the inhibitory effects of rotenoisin A on adipogenesis in 3T3-L1 preadipocytes. 3T3-L1 cells were treated with rotenoisin A for 8 days after the induction of differentiation. Oil-red O staining showed that rotenoisin A significantly inhibited DMI-induced lipid accumulation and adipocyte differentiation. We found that rotenoisin A treatment of 3T3-L1 preadipocytes significantly reduced the mRNA and protein levels of the key adipocyte-specific transcription factors C/EBPβ, C/EBPα, and PPARγ and markedly inhibited the expression of fatty acid-binding protein (aP2), fatty acid synthase (FAS), and lipoprotein lipase (LPL)...
November 7, 2018: Bioorganic & Medicinal Chemistry Letters
Lorenzo Botta, Silvia Filippi, Bruno Mattia Bizzarri, Roberta Meschini, Manuela Caputo, Luca Proietti-De-Santis, Concetta Iside, Angela Nebbioso, Giampiero Gualandi, Raffaele Saladino
Methyltrioxorhenium mediated oxidative addition/elimination nucleophilic substitution yielded alkylamino and arylamino cambinol derivatives characterized by anti-proliferative activity against wild-type and p53 mutated MGH-U1 and RT112 bladder cancer cell lines. Some of the novel compounds showed an activity higher than that of the lead compound. The reaction was highly regioselective, affording for the first time a panel of C-2 cambinol substitution products. Aliphatic primary and secondary amines, and primary aromatic amines, were used as nitrogen centered nucleophiles...
November 7, 2018: Bioorganic & Medicinal Chemistry Letters
Zhe Nie, Lihong Shi, Chon Lai, Christophe Severin, Jiangchun Xu, Joselyn R Del Rosario, Ryan K Stansfield, Robert W Cho, Toufike Kanouni, James M Veal, Jeffrey A Stafford, Young K Chen
The histone demethylase LSD1 is a key enzyme in the epigenetic regulation of gene transcription. Here we present our efforts to discover small molecule reversible inhibitors of LSD1 as an attractive approach to treat hematologic malignancies and certain solid tumors. Using structure-based drug design, we designed and synthesized a novel series of heteroaromatic imidazole inhibitors that demonstrate potent inhibition of the demethylase activity and low nanomolar cell-based activity. This novel LSD1 inhibitor series was further optimized by attenuating the hERG inhibition and improving oral bioavailability...
November 3, 2018: Bioorganic & Medicinal Chemistry Letters
Kazutaka Ikegashira, Taku Ikenogami, Takayuki Yamasaki, Yasunori Hase, Takayuki Yamaguchi, Koji Inagaki, Satoki Doi, Tsuyoshi Adachi, Yoshihisa Koga, Hiromasa Hashimoto
We report the discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by using a structure-based drug design (SBDD) based on a docking model. The work leads to the representative compound 4a with high CSF-1R inhibitory activity (IC50  = 9.1 nM). The obtained crystal structure of an azetidine compound with CSF-1R, which matched our predicted docking model, demonstrates that the azetidine compounds bind to the DFG-out conformation of the protein as a Type II inhibitor...
November 1, 2018: Bioorganic & Medicinal Chemistry Letters
Dorota Łażewska, Agnieszka Olejarz-Maciej, Maria Kaleta, Marek Bajda, Agata Siwek, Tadeusz Karcz, Agata Doroz-Płonka, Urszula Cichoń, Kamil Kuder, Katarzyna Kieć-Kononowicz
The synthesis and biological activity of 4-tert-pentylphenoxypropyl derivatives are described in this manuscript. All compounds (except one) showed human histamine H3 receptor affinity with Ki values below 760 nM. The inhibitory activity toward human monoamine oxidase B (hMAO B) was evaluated using a fluorometric Amplex-Red assay, and most of the compounds were effective in the submicromolar range. Among them, 1-(3-(4-tert-pPentylphenoxy)propyl)pyrrolidine (5) exhibited hMAO B inhibitory activity with an IC50 value of 4...
October 31, 2018: Bioorganic & Medicinal Chemistry Letters
J S Dileep Kumar, Francesca Zanderigo, Jaya Prabhakaran, Harry Rubin-Falcone, Ramin V Parsey, J John Mann
Overexpression of Cyclooxygenase-2 (COX-2) enzyme is associated with the pathogenesis of inflammation, cancers, stroke, arthritis, and neurological disorders. Because of the involvement of COX-2 in these diseases, quantification of COX-2 expression using Positron Emission Tomography (PET) may be a biological marker for early diagnosis, monitoring of disease progression, and an indicator of effective treatment. At present there is no target-specific or validated PET tracer available for in vivo quantification of COX-2...
October 31, 2018: Bioorganic & Medicinal Chemistry Letters
Jingfen Li, Dong Li, Yiming Xu, Zhenbo Guo, Xu Liu, Hua Yang, Lichuan Wu, Lisheng Wang
No abstract text is available yet for this article.
October 30, 2018: Bioorganic & Medicinal Chemistry Letters
Gejjalagere S Lingaraju, Kyathegowdanadoddi S Balaji, Shankar Jayarama, Seegehalli M Anil, Kuppalli R Kiran, Maralinganadoddi P Sadashiva
A series of new coumarin tethered isoxazolines (7a-l) were synthesized and evaluated for their cytotoxic potency against human melanoma cancer cell line (UACC 903) as well as fibroblast normal cell line (FF2441). Preliminary results revealed that some of these coumarin tethered isoxazolines 7b, 7c, 7f and 7j exhibited significant antiproliferative effect against human melanoma cancer (UACC 903) with IC50 values of 8.8, 10.5, 9.2 and 4.5 μM respectively. However, compound 7c was non-toxic to normal human cells at the tested concentration...
October 29, 2018: Bioorganic & Medicinal Chemistry Letters
Jeffrey J Letourneau, Ilana L Stroke, David W Hilbert, Andrew G Cole, Laurie J Sturzenbecker, Brett A Marinelli, Jorge G Quintero, Joan Sabalski, Yanfang Li, Linh Ma, Igor Pechik, Philip D Stein, Maria L Webb
Synthesis and structure-activity relationships (SAR) of a novel series of benzodiazepinedione-based inhibitors of Clostridium difficile toxin B (TcdB) are described. Compounds demonstrating low nanomolar affinity for TcdB, and which possess improved stability in mouse plasma vs. earlier compounds from this series, have been identified. Optimized compound 11d demonstrates a good pharmacokinetic (PK) profile in mouse and hamster and is efficacious in a hamster survival model of Clostridium difficile infection...
October 29, 2018: Bioorganic & Medicinal Chemistry Letters
Alexander Marciniak, Sara M Camp, Joe G N Garcia, Robin Polt
Sphingolipids represent an essential class of lipids found in all eukaryotes, and strongly influence cellular signal transduction. Autoimmune diseases like asthma and multiple sclerosis (MS) are mediated by the sphingosine-1-phosphate receptor 1 (S1P1 ) to express a variety of symptoms and disease patterns. Inspired by its natural substrate, an array of artificial sphingolipid derivatives has been developed to target this specific G protein-coupled receptor (GPCR) in an attempt to suppress autoimmune disorders...
October 26, 2018: Bioorganic & Medicinal Chemistry Letters
Neelima D Tangellamudi, Suchita B Shinde, Venkatesh Pooladanda, Chandraiah Godugu, Sridhar Balasubramanian
2-Aryl 5-hydroxy benzo[d]oxazoles were designed as potential anticancer agents. A one-pot synthesis of these compounds dispenses the need for ortho-disubstituted precursor, aminophenol and proceeds via CN formation as a key step followed by CO cyclization to form benzo[d]oxazoles. The single crystal X-ray diffraction study was used to confirm the molecular structure of a representative compound unambiguously. All of these compounds were evaluated for their anti-proliferative properties in vitro against five cancer cell lines as well as noncancerous cells...
October 26, 2018: Bioorganic & Medicinal Chemistry Letters
Hong Liu, Xing Dai, Shuwen He, Linda Brockunier, Karen Marcantonio, Steven W Ludmerer, Fangbiao Li, Kung-I Feng, Ravi P Nargund, Anandan Palani
Hepatitis C virus (HCV) NS5B polymerase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Several novel and potent HCV NS5B non-nucleoside inhibitors with unique tetracyclic bezonfuran-based structures were prepared and evaluated. Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species...
October 26, 2018: Bioorganic & Medicinal Chemistry Letters
Li Ping Cheng, Tian Chi Wang, Rao Yu, Meng Li, Jin Wen Huang
Neuraminidase (NA) is an important antiviral drug target. Zanamivir is one of the most potent NA inhibitors. In this paper, a series of zanamivir derivatives as potential NA inhibitors were studied by combination of molecular modeling techniques including 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation. The results show that the best CoMFA (comparative molecular field analysis) model has q2  = 0.728 and r2  = 0.988, and the best CoMSIA (comparative molecular similarity indices analysis) model has q2  = 0...
October 26, 2018: Bioorganic & Medicinal Chemistry Letters
Amit Kumar, Krista Kinneer, Luke Masterson, Ebele Ezeadi, Philip Howard, Herren Wu, Changshou Gao, Nazzareno Dimasi
Codelivery of multiple therapeutic agents with different anticancer mechanisms can overcome drug resistance as well as generate additive or synergistic anticancer effects that may enhance the antitumor efficacy. Antibody-drug conjugates (ADCs) can be used for highly specific delivery of multiple therapeutic agents with different anticancer mechanisms, though more research is required towards designing flexible platforms on which dual drug ADCs could be prepared. Herein, we describe the synthesis of a heterotrifunctional linker that could be used to construct flexible platforms for preparing dual-cytotoxic drug conjugates in a site-specific manner...
October 26, 2018: Bioorganic & Medicinal Chemistry Letters
Matthew L Hammill, Ayushi Patel, Maria Abd Alla, Jean-Paul Desaulniers
siRNAs bearing a 3'-azobenzene derivative on the sense strand were evaluated for their gene silencing ability in mammalian cell culture and nuclease stability in nuclease-rich media. Azobenzene can be isomerized between cis and trans isomers through the incubation of UV (cis isomer) and visible light (trans isomer). It was demonstrated that subtle differences in nuclease stability and activity were observed. These small changes can be used to photochemically fine-tune the activity of an siRNA for gene-silencing applications...
October 26, 2018: Bioorganic & Medicinal Chemistry Letters
Mizuki Watanabe, Takaaki Kobayashi, Yoshihiko Ito, Hayato Fukuda, Shizuo Yamada, Mitsuhiro Arisawa, Satoshi Shuto
We previously designed and synthesized a series of histamine analogues with an imidazolylcyclopropane scaffold and identified potent non-selective antagonists for histamine H3 and H4 receptor subtypes. In this study, to develop H4 selective ligands, we newly designed and synthesized cyclopropane-based derivatives having an indole, benzimidazole, or piperazine structure, which are components of representative H4 selective antagonists such as JNJ7777120 and JNJ10191584. Among the synthesized derivatives, imidazolylcyclopropanes 12 and 13 conjugated with a benzimidazole showed binding affinity to the H3 and H4 receptors comparable to that of a well-known non-selective H3 /H4 antagonist, thioperamide...
October 26, 2018: Bioorganic & Medicinal Chemistry Letters
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