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Journal of Medicinal Chemistry

Jared T Hammill, Daniel C Scott, Jaeki Min, Michele C Connelly, Gloria Holbrook, Fangyi Zhu, Amy Matheny, Lei Yang, Bhuvanesh Singh, Brenda A Schulman, R Kiplin Guy
We previously discovered and validated a class of piperidinyl ureas that regulate defective in cullin neddylation 1 (DCN1)-dependent neddylation of cullins. Here, we report preliminary structure-activity relationship studies aimed at advancing our high-throughput screen hit into a tractable tool compound for dissecting the effects of acute DCN1-UBE2M inhibition on the NEDD8/cullin pathway. Structure-enabled optimization led to a 100-fold increase in biochemical potency and modestly increased solubility and permeability as compared to our initial hit...
March 16, 2018: Journal of Medicinal Chemistry
Jared T Hammill, Deepak Bhasin, Daniel C Scott, Jaeki Min, Yizhe Chen, Yan Lu, Lei Yang, Ho Shin Kim, Michele C Connelly, Courtney Hammill, Gloria Holbrook, Cynthia Jeffries, Bhuvanesh Singh, Brenda A Schulman, R Kiplin Guy
We previously reported the discovery, validation, and structure-activity relationships of a series of piperidinyl ureas that potently inhibit the DCN1-UBE2M interaction. We demonstrated that compound 7 inhibits both the DCN1-UBE2M protein-protein interaction and DCN1-mediated cullin neddylation in biochemical assays and reduces levels of steady-state cullin neddylation in a squamous carcinoma cell line harboring DCN1 amplification. Although compound 7 exhibits good solubility and permeability, it is rapidly metabolized in microsomal models (CLint = 170 mL/min/kg)...
March 16, 2018: Journal of Medicinal Chemistry
Ana Trapero, Angela Pacitto, Vinayak Singh, Mohamad Sabbah, Anthony G Coyne, Valerie Mizrahi, Tom L Blundell, David B Ascher, Chris Abell
Tuberculosis (TB) remains a major cause of mortality worldwide, and improved treatments are needed to combat emergence of drug resistance. Inosine 5´-monophosphate dehydrogenase (IMPDH), a crucial enzyme required for de novo synthesis of guanine nucleotides, is an attractive TB drug target. Herein, we describe the identification of potent IMPDH inhibitors using fragment-based screening and structure-based design techniques. Screening of a fragment library for Mycobacterium thermoresistible (Mth) IMPDH(ΔCBS) inhibitors identified a low affinity phenylimidazole derivative...
March 16, 2018: Journal of Medicinal Chemistry
Jean-Francois Fournier, Claire Bouix-Peter, Denis Duvert, Anne-Pascale Luzy, Gilles Ouvry
Phototoxicity occurs when UV irradiation causes otherwise benign compounds to become irritant, sensitizers or even genotoxic. This toxicity is particularly a concern after topical application and in dermatological programs where skin irritation can be incompatible with the desired therapeutic outcome. This brief article establishes that the intrinsic Property Forecast Index (iPFI) can be used to evaluate the probability of a compound being phototoxic and gives medicinal chemists a practical tool to handle this liability...
March 16, 2018: Journal of Medicinal Chemistry
Michael K Krapf, Jennifer Gallus, Sahel Vahdati, Michael Wiese
Multidrug resistance occurring during cancer chemotherapy is a major obstacle for effectiveness and response to therapy and is often caused by ATP-binding cassette (ABC) efflux transporters. Belonging to the family of ABC transporters, breast cancer resistance protein is getting more and more in the spotlight of research. As a strategy to overcome multidrug resistance, inhibitors of ABC transporters were synthesized, which could be applied in combination with cytostatic drugs. For this purpose, 2,4-disubstituted pyridopyrimidine derivatives were synthesized...
March 16, 2018: Journal of Medicinal Chemistry
Juliana C C Dallagnol, Elham Khajehali, Emma T van der Westhuizen, Manuela Jörg, Celine Valant, Alan G Goncalves, Ben Capuano, Arthur Christopoulos, Peter J Scammells
Targeting allosteric sites at M1 muscarinic acetylcholine receptors is a promising strategy for the treatment of Alzheimer's disease. Positive allosteric modulators may not only potentiate binding and/or signaling of the endogenous agonist acetylcholine (ACh), but may also possess direct agonist activity (thus referred to as PAM-agonists). Recent studies suggest that PAM-agonists with robust intrinsic efficacy are more likely to produce adverse effects in vivo. Herein we present the synthesis and pharmacological evaluation of a series of pyrrole-3-carboxamides with a diverse range of allosteric profiles...
March 15, 2018: Journal of Medicinal Chemistry
Martina Gobec, Tihomir Tomašič, Adela Štimac, Ruža Frkanec, Jurij Trontelj, Marko Anderluh, Irena Mlinaric-Rascan, Žiga Jakopin
Muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, has long been known as the smallest fragment possessing adjuvant activity, on the basis of its agonistic action on the nucleotide-binding oligomerization domain-containing protein 2 (NOD2). There is a pressing need for novel adjuvants and NOD2 agonists provide an untapped source of potential candidates. Here, we report the design, synthesis and characterization of a series of novel acyl tripeptides. A pivotal structural element for molecular recognition by NOD2 has been identified, culminating in the discovery of compound 9, the most potent desmuramylpeptide NOD2 agonist to date...
March 15, 2018: Journal of Medicinal Chemistry
Prama Pallavi, Marc Pretze, Julio Caballero, Yingchun Li, Björn B Hofmann, Eleni Stamellou, Sarah Klotz, Carmen Wängler, Björn Wängler, Ralf Loesel, Steffen Roth, Bastian Theisinger, Handan Moerz, Uta Binzen, Wolfgang Greffrath, Rolf-Detlef Treede, Martin C Harmsen, Bernhard K Krämer, Mathias Hafner, Benito A Yard, Anna-Isabelle Kälsch
We studied the chemical entities within N-octanoyl dopamine (NOD) responsible for transient receptor potential channels of the vanilloid receptor subtype 1 (TRPV1) activation and inhibition of inflammation. The efficacy of NOD to activate TRPV1 was significantly higher compared to variants in which the ortho-dihydroxy groups were acetylated, one of the hydroxy groups was omitted (N-octanoyl tyramine) or the ester functionality consisted of a bulky fatty acid (N-pivaloyl dopamine). Shortening of the amide linker (ΔNOD) slightly increased its efficacy which further increased by interchanging the carbonyl and amide groups (ΔNODR)...
March 15, 2018: Journal of Medicinal Chemistry
John R Horton, Xu Liu, Lizhen Wu, Kai Zhang, John Shanks, Xing Zhang, Ganesha Rai, Bryan T Mott, Daniel J Jansen, Stephen C Kales, Mark J Henderson, Katherine Pohida, Yuhong Fang, Xin Hu, Ajit Jadhav, David J Maloney, Matthew D Hall, Anton Simeonov, Haian Fu, Paula M Vertino, Qin Yan, Xiaodong Cheng
Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely (R)- and (S)-2-((2-chlorophenyl)(2-(piperidin-1-yl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (compounds N51 and N52) and (R)- and (S)-N-(1-(3-isopropyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropane-carboxamide (compounds N54 and N55)...
March 14, 2018: Journal of Medicinal Chemistry
Hua Lin, Jonathan Z Long, Alexander M Roche, Katrin J Svensson, Florence Dou, Mi Ra Chang, Timothy Strutzenberg, Claudia Ruiz, Michael D Cameron, Scott J Novick, Charles M Berdan, Sharon Louie, Daniel K Nomura, Bruce M Spiegelman, Patrick R Griffin, Theodore M Kamenecka
N-acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure indicating that this pathway might be useful for treating obesity and associated disorders. We report the full account of the synthesis and mitochondrial uncoupling bioactivity of lipidated N-acyl amino acids and their unnatural analogs. Unsaturated fatty acid chains of medium length and neutral amino acid head groups are required for optimal uncoupling activity on mammalian cells...
March 13, 2018: Journal of Medicinal Chemistry
Ye Ding, Dengfeng Li, Chunyong Ding, Pingyuan Wang, Zhiqing Liu, Eric A Wold, Na Ye, Haiying Chen, Mark Andrew White, Qiang Shen, Jia Zhou
Covalent drug discovery has undergone a resurgence in recent years due to comprehensive optimization of structure-activity relationship (SAR) and structure-reactivity relationship (SRR) for covalent drug candidates. The natural product oridonin maintains an impressive pharmacological profile through its covalent enone warhead on the D-ring and has attracted substantial SAR studies to characterize its potential in the development of new molecular entities for the treatment of various human cancers and inflammation...
March 12, 2018: Journal of Medicinal Chemistry
Nanette L S Que, Vincent M Crowley, Adam S Duerfeldt, Jinbo Zhao, Caitlin N Kent, Brian S J Blagg, Daniel T Gewirth
Grp94 and Hsp90, the ER and cytoplasmic hsp90 paralogs, share a conserved ATP-binding pocket that has been targeted for therapeutics. Paralog-selective inhibitors may lead to drugs with fewer side effects. Here, we analyzed 1 (BnIm), a benzyl imidazole resorcinylic inhibitor, for its mode of binding. The structures of 1 bound to Hsp90 and Grp94 reveal large conformational changes in Grp94, but not Hsp90 that expose Site 2, a binding pocket adjacent to the central ATP cavity that is ordinarily blocked. The Grp94:1 structure reveals a flipped pose of the resorcinylic scaffold that inserts into the exposed Site 2...
March 12, 2018: Journal of Medicinal Chemistry
Pengyu Yang, Huafei Zou, Candy Lee, Avinash Muppidi, Elizabeth Chao, Qiangwei Fu, Xiaozhou Luo, Danling Wang, Peter G Schultz, Weijun Shen
Glucagon-like peptide 2 (GLP-2) is a hormone that has been shown to stimulate intestinal growth and attenuate intes-tinal inflammation. Despite being efficacious in a variety of animal models of disease, its therapeutic potential is ham-pered by the short half-life in vivo. We now describe a highly potent, stapled long-acting GLP-2 analog, Peptide 10, that has a more than 10-fold longer half-life than teduglutide and improved intestinotrophic and anti-inflammatory effects in mouse models of DSS-induced colitis...
March 12, 2018: Journal of Medicinal Chemistry
Morane Le Hiress, Bernardin Akagah, Guillaume Bernadat, Ly Tu, Raphaël Thuillet, Alice Huertas, Carole Phan, Elie Fadel, Gérald Simonneau, Marc Humbert, Gaël Jalce, Christophe Guignabert
Macrophage migration inhibitory factor (MIF) is a key pleiotropic mediator and a promising therapeutic target in cancer as well as in several inflammatory and cardiovascular diseases including pulmonary arterial hypertension (PAH). Here, a novel series of N-(phenylmethyl)-benzoxazol-2-thiones 5-32 designed to target the MIF tautomerase active site was synthesized and evaluated for its effects on cell survival. Investigation of structure-activity relationship (SAR) particularly at the 5-position of the benzoxazole core led to the identification of 31 that potently inhibits cell survival in DU-145 prostate cancer cells and pulmonary endothelial cells derived from patients with idiopathic PAH (iPAH-ECs), two cell lines for which survival is MIF-dependent...
March 10, 2018: Journal of Medicinal Chemistry
Siegfried H Reich, Paul A Sprengeler, Gary G Chiang, Jim R Appleman, Joan Chen, Jeff Clarine, Boreth Eam, Justin T Ernst, Qing Han, Vikas K Goel, Edward Zr Han, Vera Huang, Ivy Nj Hung, Adrianna Jemison, Katti A Jessen, Jolene Molter, Douglas Murphy, Melissa Neal, Gregory S Parker, Michael Shaghafi, Samuel Sperry, Jocelyn Staunton, Craig R Stumpf, Peggy A Thompson, Chinh Tran, Stephen E Webber, Christopher J Wegerski, Hong Zheng, Kevin R Webster
Dysregulated translation of mRNA plays a major role in tumorigenesis. MNK1/2 kinases are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA which control tumor/stromal cell signaling. 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation...
March 10, 2018: Journal of Medicinal Chemistry
Diego Brancaccio, Donatella Diana, Salvatore Di Maro, Francesco Saverio Di Leva, Stefano Tomassi, Roberto Fattorusso, Luigi Russo, Stefania Scala, Anna Maria Trotta, Luigi Portella, Ettore Novellino, Luciana Marinelli, Alfonso Carotenuto
Peptides-binding G protein-coupled receptors play an important role in many pathological and physiological pathways. The assessment of the receptor-bound conformation of a peptidic ligand within a membrane receptor such as a GPCR is of outmost importance for a rational drug design of more potent analogues. In this work, we applied multiple ligand-based NMR methods to study the interaction of peptide heptamers, derived from the C-X-C Motif Chemokine 12 (CXCL12), and the C-X-C Chemokine Receptor Type 4 (CXCR4) on membranes of human T-Leukemia cells (CCRF-CEM cells)...
March 9, 2018: Journal of Medicinal Chemistry
Yuming Wang, Lijun Li, Jun Fan, Yang Dai, Alan Jiang, Mei-Yu Geng, Jing Ai, Wenhu Duan
Fibroblast growth factor receptors (FGFR1-4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2)...
March 9, 2018: Journal of Medicinal Chemistry
Meixi Hao, Siyuan Hou, Lingjing Xue, Haoliang Yuan, Lulu Zhu, Cong Wang, Bin Wang, Chunming Tang, Can Zhang
Vitamin D3 receptor (VDR), belonging to the nuclear receptor superfamily, is a potential molecular target for anticancer drug discovery. In this study, a series of non-steroidal vitamin D analogs with phenyl-pyrrolyl pentane skeleton were synthesized with therapeutic potential for cancer treatment. Among them, 11b and 11g were identified as the most effective agents in reducing the viability of four cancer cell lines, particularly breast cancer cells, with IC50 values in the submicromolar concentration range...
March 8, 2018: Journal of Medicinal Chemistry
Yongtao Li, Xiaohe Luo, Qingxiang Guo, Yongwei Nie, Tianqi Wang, Chao Zhang, Zhi Huang, Xin Wang, Yanhua Liu, Yanan Chen, Jian-Yu Zheng, Shengyong Yang, Yan Fan, Rong Xiang
A series of novel, highly potent, selective inhibitors targeting both CDK4/9 and HDAC1 have been designed and synthesized. N1-(4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d] pyrimidin-2-yl) amino) phenyl)-N8-hydroxyoctanediamide (6e) was discovered. The lead compound 6e with excellent CDK4/9 and HDAC1 inhibitory activity of IC50 = 8.8 nM, 12 nM and 2.2 nM respectively, can effectively induce apoptosis of cancer cell lines. The kinase profiling of compound 6e showed excellent selectivity and specificity...
March 8, 2018: Journal of Medicinal Chemistry
Daniel P Teufel, Gavin Bennett, Helen Harrison, Katerine van Rietschoten, Silvia Pavan, Catherine Stace, François Le Floch, Tine Van Bergen, Elke Vermassen, Philippe Barbeaux, Tjing-Tjing Hu, Jean H M Feyen, Marc Vanhove
Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability and pain. Preclinical evidence implicates the activity of plasma kallikrein in diabetic retinopathy, which is a leading cause of visual loss in patients suffering from diabetes mellitus. Employing a technology based on phage-display combined with chemical cyclization, we have identified highly selective bicyclic peptide inhibitors with nano- and pico-molar potencies towards plasma kallikrein...
March 8, 2018: Journal of Medicinal Chemistry
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