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Journal of Medicinal Chemistry

Romain Siegrist, Davide Pozzi, Gaël Jacob, Caterina Torrisi, Kilian Colas, Bertrand Braibant, Jacques Mawet, Thomas Pfeifer, Ruben de Kanter, Catherine Roch, Melanie Kessler, Richard Moon, Olivier Corminboeuf, Olivier Bezençon
No abstract text is available yet for this article.
February 24, 2017: Journal of Medicinal Chemistry
Pär Matsson, Jan Kihlberg
Understanding how to design cell permeable ligands for intracellular targets that have difficult binding sites, such as protein-protein interactions, would open vast opportunities for drug discovery. Interestingly, libraries of cyclic peptides displayed a steep drop-off in membrane permeability at molecular weights above 1000 Da and it appears likely that this cutoff constitutes an upper size limit also for more druglike compounds. However, chemical space from 500 to 1000 Da remains virtually unexplored and represents a vast opportunity for those prepared to venture into new territories of drug discovery...
February 24, 2017: Journal of Medicinal Chemistry
Yong-Jin Wu, Jason Guernon, Jianliang Shi, Jonathan Ditta, Kevin J Robbins, Ramkumar Rajamani, Amy Easton, Amy E Newton, Clotilde Bourin, Kathleen Mosure, Matthew G Soars, Ronald J Knox, Michele Matchett, Rick L Pieschl, Debra J Post-Munson, Shuya Wang, James Herrington, John Graef, Kimberly Newberry, Linda J Bristow, Nicholas A Meanwell, Richard E Olson, Lorin A Thompson, Carolyn D Dzierba
By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Nav1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient DRG exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO but, confoundingly, only one of these was effective in the formalin test...
February 24, 2017: Journal of Medicinal Chemistry
Gang Wang, Hong-Xiang Chen, Dong-Yang Zhao, Da-Wei Ding, Mengchi Sun, Long-Fa Kou, Cong Luo, Dong Zhang, Xiu-Lin Yi, Jinhua Dong, Jian Wang, Xiaohong Liu, Zhonggui He, Jin Sun
The new organic cation transporter 2 (OCTN2, SLC22A5) is responsible for the uptake of carnitine through the intestine and, therefore, it may be a promising molecular target for designing oral prodrugs. Poor permeability and rapid metabolism have greatly restricted the oral absorption of gemcitabine. We here describe the design of intestinal OCTN2-targeting prodrugs of gemcitabine by covalent coupling of L-carnitine to its N4-amino group via different lipophilic linkages. Due to high OCTN2 affinity, the hexane diacid-linked prodrug demonstrated significantly improved stability (3-fold), cellular permeability (15-fold), and then increased oral bioavailability (5-fold), while causing no toxicity as compared to gemcitabine...
February 24, 2017: Journal of Medicinal Chemistry
Van-Hai Hoang, Phuong-Thao Tran, Minghua Cui, Van T H Ngo, Jihyae Ann, Jongmi Park, Jiyoun Lee, Kwanghyun Choi, Hanyang Cho, Hee Kim, Heejin Ha, Hyun-Seok Hong, Sun Choi, Young-Ho Kim, Jeewoo Lee
Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of β-amyloid peptides (pGlu-Aβ), thus may participate in the pathogenesis of Alzheimer's disease. We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, Aβ3E-42. An in vitro structure-activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor...
February 24, 2017: Journal of Medicinal Chemistry
Xin Chen, John Giraldes, Elizabeth R Sprague, Subarna Shakya, Zhuoliang Chen, Yaping Wang, Carol Joud, Simon Mathieu, Christine Hiu-Tung Chen, Christopher Straub, Jose Duca, Kristen Hurov, Yanqiu Yuan, Wenlin Shao, B Barry Touré
While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improving the kinase selectivity of type II maternal embryonic leucine zipper kinase inhibitors by applying these two complementary approaches together, which clearly demonstrates the powerful synergy between them...
February 24, 2017: Journal of Medicinal Chemistry
Hui-Li Ng, Xiang Ma, Eng-Hui Chew, Wai-Keung Chui
The dihydrofolate reductase (DHFR) and thioredoxin reductase (TrxR) enzymes are involved in the process of tumor cell growth and survival. The 4,6-diamino-1,2-dihydro-1,3,5-triazine scaffold is well-established as a useful scaffold for DHFR inhibition, while chalcones have been reported to be inhibitors of TrxR. In this study, 15 novel compounds designed by the structural combination of the 4,6-diamino-1,2-dihydro-1,3,5-triazine and chalcone scaffolds via a diether linker were successfully synthesized and characterized...
February 24, 2017: Journal of Medicinal Chemistry
Mark E Schnute, Matthew D McReynolds, Jeffrey Carroll, Jill E Chrencik, Maureen K Highkin, Kaliapan Iyanar, Gina Jerome, John W Rains, Matthew Saabye, Jeffrey A Scholten, Matthew Yates, Marek M Nagiec
Sphingosine kinase (SphK) is the major source of the lipid mediator and GPCR agonist sphingosine-1-phosphate (S1P). S1P promotes cell growth, survival and migration and is a key regulator of lymphocyte trafficking. Inhibition of S1P signaling has been proposed as a strategy for treatment of inflammatory diseases and cancer. Two different formats of an enzyme based high-throughput screen yielded two attractive chemotypes capable of inhibiting S1P formation in cells. The molecular combination of these screening hits led to compound 22a (PF-543) with two orders of magnitude improved potency...
February 23, 2017: Journal of Medicinal Chemistry
Xiujing Dou, Xin Zhu, Jiajun Wang, Na Dong, Anshan Shan
Coiled-coil, a basic folding pattern of native proteins, was previously demonstrated to be associated with the specific spatial recognition, association, and dissociation of proteins and can be used to perfect engineering peptide model. Thus, in this study, a series of amphiphiles composed of heptads repeats with coiled-coil structures was constructed, and the designed peptides exhibited a broad spectrum of antimicrobial activities. Circular dichroism and biological assays showed that the heptad repeats and length of the linker between the heptads largely influenced the amphiphile's helical propensity and cell selectivity...
February 23, 2017: Journal of Medicinal Chemistry
Yifu Liu, Zuoquan Xie, Dan Zhao, Jin Zhu, Fei Mao, Shuai Tang, Hui Xu, Cheng Luo, Mei-Yu Geng, Min Huang, Jian Li
Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described Bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, based on the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analog, 3a, effectively inhibits PDK1 both at the molecular (kinact/Ki = 4.17×103M-1s-1) and the cellular level (down to 0.1 μM). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4...
February 23, 2017: Journal of Medicinal Chemistry
Vibha Pathak, Corinne Elizabeth Augelli-Szafran, Han-Xun Wei, Yonghe Li, Patsy G Oliver, Wenyan Lu, Donald J Buchsbaum, Mark J Suto
Wnt/beta-Catenin signaling pathway has a very important role in pancreatic ductal adenocarcinoma (PDAC) initiation and progression. This signaling pathway has been implicated in angiogenesis, maintenance of resistant CICs (cancer-initiating cells), metastasis, regulation of cell cycle, apoptosis and chemoresistance. We investigated the activity of a chemical series of phenyl benzimidazoles, small molecule inhibitors of Wnt signaling in LRP6-expressing HEK 293 cells against PDAC cells. Several benzimidazoles were designed, synthesized and screened under adherent and CIC conditions...
February 23, 2017: Journal of Medicinal Chemistry
Matthew G Bursavich, Bryce A Harrison, Raksha Acharya, Donald E Costa, Emily A Freeman, Hilliary E Hodgdon, Lori A Hrdlicka, Hong Jin, Sudarshan Kapadnis, Jeffrey S Moffit, Deirdre A Murphy, Scott Nolan, Holger Patzke, Cuyue Tang, Melody Wen, Gerhard Koenig, Jean-François Blain, Duane A Burnett
Herein we describe the design, synthesis and evaluation of a novel series of oxadiazine-based gamma secretase modulators obtained via isosteric amide replacement and critical consideration of conforma-tional restriction. Oxadiazine lead 47 possesses good in vitro potency with excellent predicted CNS drug-like properties and desirable ADME/PK profile. This lead compound demonstrated robust Aβ42 reductions and subsequent Aβ37 increases in both rodent brain and CSF at 30 mg/kg dosed orally.
February 23, 2017: Journal of Medicinal Chemistry
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 1,780 prescription drugs by combining in silico and in vitro methods. Ligands were predicted by docking against a comparative model based a eukaryotic homolog. In parallel, high-throughput screening (HTS) was conducted using the fluorescent probe substrate ASP+ in cells overexpressing human OCT1...
February 23, 2017: Journal of Medicinal Chemistry
Jung-Ho Son, Jie S Zhu, Puay-Wah Phuan, Onur Cil, Andrew P Teuthorn, Colton K Ku, Sujin Lee, Alan S Verkman, Mark J Kurth
We previously identified phenylquinoxalinone CFTRact-J027 (4) as a cystic fibrosis transmembrane conductance regulator (CFTR) activator with an EC50 of ~200 nM, and demonstrated its therapeutic efficacy in mouse models of constipation. Here, structure-activity studies were done on 36 synthesized phenylquinoxalinone analogs to identify compounds with improved potency and altered metabolic stability. Synthesis of the phenylquinoxalinone core was generally accomplished by condensation of 1,2-phenylenediamines with substituted phenyloxoacetates...
February 23, 2017: Journal of Medicinal Chemistry
Kimito Kimura, Yoshihisa Hirota, Shigefumi Kuwahara, Atsuko Takeuchi, Chisato Tode, Akimori Wada, Naomi Osakabe, Yoshitomo Suhara
We synthesized novel vitamin K2 analogues that incorporated a heteroatom and an aromatic ring in the side chain and evaluated their effect on the selective differentiation of neuronal progenitor cells into neurons in vitro. The result showed that a menaquinone-2 analogue bearing a p-fluoroaniline had the most potent activity, which was more than twice as great as the control. In addition, the neuronal selectivity was more than three times greater than the control.
February 22, 2017: Journal of Medicinal Chemistry
Ahmed Al-Sabi, Declan Daly, Patrick Hoefer, Gemma K Kinsella, Charles P E Metais, Mark Pickering, Caroline Herron, Seshu Kumar Kaza, Kieran J Nolan, J Oliver Dolly
K(+) channels containing Kv1.1 α subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarising K(+) currents. Modelling of interactions with the extracellular pore in a Kv1.1 deduced-structure identified a diaryldi-(2-pyrrolyl)methane (DPM) as a suitable scaffold, with optimised alkyl ammonium side chains. The resultant synthesised candidate [2,2'-((5,5'(di-p-topyldiaryldi-(2-pyrrolyl)methane)bis(2,2'carbonyl)bis (azanediyl)) diethaneamine...
February 22, 2017: Journal of Medicinal Chemistry
Stefano Tomassi, Jonas Lategahn, Julian Engel, Marina Keul, Hannah Lea Tumbrink, Julia Ketzer, Thomas Mühlenberg, Matthias Baumann, Carsten Schultz-Fademrecht, Sebastian Bauer, Daniel Rauh
The specific targeting of oncogenic mutant epidermal growth factor receptor (EGFR) is a breakthrough in targeted cancer therapy and marks a drastic change in the treatment of non-small cell lung cancer (NSCLC). The recurrent emergence of resistance to these targeted drugs requires the development of novel chemical entities that efficiently inhibit drug-resistant EGFR. Herein, we report the optimization process for a hit compound that has emerged from a phenotypic screen resulting in indazole-based compounds...
February 22, 2017: Journal of Medicinal Chemistry
Yiqing Yang, You Yu, Xiaolu Li, Jing Li, Yue Wu, Jie Yu, Jingpeng Ge, Zhenghui Huang, Lubin Jiang, Yu Rao, Maojun Yang
Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new antimalarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for antimalarial drug development. However, the absence of structural information on PfNDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the PfNDH2 protein for the first time in Apo-, NADH-, and RYL-552 (a new inhibitor)-bound states...
February 22, 2017: Journal of Medicinal Chemistry
Joris W De Schutter, James P Morrison, Michael J Morrison, Alessio Ciulli, Barbara Imperiali
The glycoproteins of selected microbial pathogens often include highly modified carbohydrates such as 2,4-diacetamidobacillosamine (diNAcBac). These glycoconjugates are involved in host-cell interactions and may be associated with the virulence of medically significant Gram-negative bacteria. In light of genetic studies demonstrating the attenuated virulence of bacterial strains in which modified carbohydrate biosynthesis enzymes have been knocked out, we are developing small molecule inhibitors of selected enzymes as tools to evaluate whether such compounds modulate virulence...
February 22, 2017: Journal of Medicinal Chemistry
Cristina Travelli, Silvio Aprile, Reza Rahimian, Ambra A Grolla, Federica Rogati, Mattia Bertolotti, Floriana Malagnino, Rosanna di Paola, Daniela Impellizzeri, Roberta Fusco, Valentina Mercalli, Alberto Massarotti, Giorgio Stortini, Salvatore Terrazzino, Erika Del Grosso, Gohar Fakhfouri, Maria Pia Troiani, Maria Alessandra Alisi, Giorgio Grosa, Giovanni Sorba, Pier Luigi Canonico, Giuseppe Orsomando, Salvatore Cuzzocrea, Armando A Genazzani, Ubaldina Galli, Gian Cesare Tron
Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme involved in the recycling of nicotinamide to maintain adequate NAD levels inside the cells. It has been postulated to be a pharmacological target, as it is overexpressed in cancer cells as well as in inflammatory diseases. We describe the synthesis and characterization of a novel class of one-digit nanomolar NAMPT inhibitors based on in vitro characterization. The most active compound tested, 30c, displayed activity in xenograft and allograft models, strengthening the potential of NAMPT inhibitors as antitumoral drugs...
February 22, 2017: Journal of Medicinal Chemistry
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