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ACS Medicinal Chemistry Letters

Catherine Fagundez, Diver Sellanes, Stella Peña, Laura Scarone, Anna C C Aguiar, Juliana O de Souza, Rafael V C Guido, Lindsay Stewart, Vanessa Yardley, Sabine Ottilie, Elizabeth A Winzeler, Francisco-J Gamo, Laura M Sanz, Gloria L Serra
Malaria is a major tropical disease where important needs are to mitigate symptoms and to prevent the establishment of infection. Cyclopeptides containing N -methyl amino acids with in vitro activity against erythrocytic forms as well as liver stage are presented. The synthesis, parasitological characterization, physicochemical properties, in vivo evaluation, and mice pharmacokinetics are described.
January 10, 2019: ACS Medicinal Chemistry Letters
Ziwei Hu, Janardhan Banothu, Mallesh Beesu, Collin J Gustafson, Michael J H Brush, Kathryn L Trautman, Alex C D Salyer, Balaji Pathakumari, Sunil A David
Using a multiplexed, reporter gene-based, high-throughput screen, we identified 9-fluoro-7-hydroxy-3-methyl-5-oxo- N -(pyridin-3-ylmethyl)-2,3-dihydro-1 H ,5 H -pyrido[3,2,1-ij]quinoline-6-carboxamide as a TLR2 agonist. Preliminary structure-activity relationship studies on the carboxamide moiety led to the identification of analogues that induce chemokines and cytokines in a TLR2-dependent manner. These results represent new leads for the development of vaccine adjuvants.
January 10, 2019: ACS Medicinal Chemistry Letters
Yong Ai, Obinna N Obianom, Meredith Kuser, Yue Li, Yan Shu, Fengtian Xue
We report the design, synthesis, and evaluation of novel 5-fluorouracil (5FU) prodrugs 1a , 1b that are efficiently activated by the high level of reactive oxygen species (ROS) in cancer cells. Prodrugs 1a , 1b selectively kill cancer cells over normal cells and are well-tolerated in mice. The strategy described herein can extend application of chemotherapeutic drugs.
January 10, 2019: ACS Medicinal Chemistry Letters
Mark W Majewski, Disha M Gandhi, Ricardo Rosas, Revathi Kodali, Leggy A Arnold, Chris Dockendorff
A novel class of bivalent ligands targeting putative protease-activated receptor (PAR) heteromers has been prepared based upon reported antagonists for the subtypes PAR1 and PAR2. Modified versions of the PAR1 antagonist RWJ-58259 containing alkyne adapters were connected via cycloaddition reactions to azide-capped polyethylene glycol (PEG) spacers attached to imidazopyridazine-based PAR2 antagonists. Initial studies of the PAR1-PAR2 antagonists indicated that they inhibited G alpha q-mediated calcium mobilization in endothelial and cancer cells driven by both PAR1 and PAR2 agonists...
January 10, 2019: ACS Medicinal Chemistry Letters
Philip N Collier, Advaita Panchagnula, Hardwin O'Dowd, Arnaud Le Tiran, Alex M Aronov
Phosphoinositide 3-kinase (PI3Kγ) is a drug target that has been implicated in the treatment of a range of diseases. We have developed a synthesis of a novel PI3Kγ inhibitor containing a 1,2-dihydro-3H-pyrrolo[3,4- c ]pyridin-3-one scaffold. The key step in the synthesis involved a ruthenium-catalyzed [2 + 2 + 2] cyclotrimerization reaction between a diyne and an alkoxycarbonyl isocyanate, a previously unreported coupling partner in such a reaction.
January 10, 2019: ACS Medicinal Chemistry Letters
J Matthew Meinig, Skylar J Ferrara, Tapasree Banerji, Tania Banerji, Hannah S Sanford-Crane, Dennis Bourdette, Thomas S Scanlan
Thyroid hormone (TH) action is of clinical interest in treating demyelinating diseases of the central nervous system (CNS). Two amide prodrugs of sobetirome, a potent thyroid hormone agonist, were previously shown to significantly improve CNS selective distribution of the parent drug through hydrolysis in the CNS by fatty acid amide hydrolase (FAAH). This concept is elaborated upon here with a series of 29 amide prodrugs targeting FAAH. We identify that conservative aliphatic modifications such as the N -methyl ( 4 ), N -ethyl ( 5 ), N -fluoroethyl ( 15 ), and N -cyclopropyl ( 18 ) substantially favor selective CNS distribution of the parent drug in mice...
January 10, 2019: ACS Medicinal Chemistry Letters
Pendem Nagendar, J Robert Gillespie, Zackary M Herbst, Ranae M Ranade, Nora M R Molasky, Omeed Faghih, Rachael M Turner, Michael H Gelb, Frederick S Buckner
Better therapeutics are greatly needed to treat patients infected with trypanosomatid parasites such as Trypanosoma cruzi or Trypanosoma brucei . This report describes 28 new imidazopyridines and triazolopyrimidines with potent and selective antitrypanosomal activity. Drug-like properties were demonstrated in a number of in vitro assays. In vivo efficacy was observed for 19 and 20 in acute mouse models of T. cruzi infection. Compounds 19 and 20 represent potential leads for new anti-Chagas disease drugs.
January 10, 2019: ACS Medicinal Chemistry Letters
Alexios N Matralis, Angeliki P Kourounakis
Among the causal risk factors directly promoting the development of coronary and peripheral atherosclerosis are reactive oxygen species and elevated low-density lipoprotein plasma levels. We hereby designed new potent squalene synthase (SQS) inhibitors that may simultaneously tackle the oxidative stress induced by lipid peroxidation. Using previously developed morpholine derivatives as a starting point, we conducted extensive structural changes by either substituting or modifying the morpholine ring, aiming at an optimal SQS-antioxidant pharmacological profile...
January 10, 2019: ACS Medicinal Chemistry Letters
Tony Siu, Michael D Altman, Gretchen A Baltus, Matthew Childers, J Michael Ellis, Hakan Gunaydin, Harold Hatch, Thu Ho, James Jewell, Brian M Lacey, Charles A Lesburg, Bo-Sheng Pan, Berengere Sauvagnat, Gottfried K Schroeder, Serena Xu
Drugging large protein pockets is a challenge due to the need for higher molecular weight ligands, which generally possess undesirable physicochemical properties. In this communication, we highlight a strategy leveraging small molecule active site dimers to inhibit the large symmetric binding pocket in the STING protein. By taking advantage of the 2:1 binding stoichiometry, maximal buried interaction with STING protein can be achieved while maintaining the ligand physicochemical properties necessary for oral exposure...
January 10, 2019: ACS Medicinal Chemistry Letters
R Murray McKinnell, Paul Fatheree, Seok-Ki Choi, Roland Gendron, Keith Jendza, Brooke Olson Blair, Joe Budman, Craig M Hill, Laxminarayan G Hegde, Cecile Yu, Donavon McConn, Sharath S Hegde, Daniel G Marquess, Uwe Klein
Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy relative to ACE inhibitors but is associated with a higher risk of life-threatening angioedema due to bradykinin elevations. We hypothesized that dual AT1 (angiotensin II type 1 receptor) blockade and NEP inhibition with a single molecule would produce similar antihypertensive efficacy to omapatrilat without the risk of angioedema since ACE (the rate limiting enzyme in bradykinin metabolism) would remain uninhibited...
January 10, 2019: ACS Medicinal Chemistry Letters
Mark E Schnute, Stephen E Benoit, Ingrid P Buchler, Nicole Caspers, Margaret L Grapperhaus, Seungil Han, Rajeev Hotchandani, Nelson Huang, Robert O Hughes, Brian M Juba, Kyung-Hee Kim, Erica Liu, Erin McCarthy, Dean Messing, Joy S Miyashiro, Shashi Mohan, Thomas N O'Connell, Jeffrey F Ohren, Mihir D Parikh, Michelle Schmidt, Shaun R Selness, John R Springer, Venkataraman Thanabal, John I Trujillo, Daniel P Walker, Zhao-Kui Wan, Jane M Withka, Arthur J Wittwer, Nancy L Wood, Li Xing, Christoph W Zapf, John Douhan
Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties...
January 10, 2019: ACS Medicinal Chemistry Letters
Rory K Morgan, Ilsa T Kirby, Anke Vermehren-Schmaedick, Kelsie Rodriguez, Michael S Cohen
Poly-ADP-ribose polymerases (PARPs 1-16) have emerged as major regulators of diverse cellular processes. PARPs can be subclassified based on their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). While much is known about the cellular roles of PARPs that catalyze PARylation (e.g., PARP1), the function of PARPs that catalyze MARylation (e.g., PARP10) is substantially less understood. This is due in large part to the lack of small-molecule inhibitors that are selective for individual PARP family members that catalyze MARylation...
January 10, 2019: ACS Medicinal Chemistry Letters
Brooke M Katzman, Bryan D Cox, Anthony R Prosser, Ana A Alcaraz, Brigitte Murat, Madeleine Héroux, Andrew Tebben, Yong Zhang, Gretchen M Schroeder, James P Snyder, Lawrence J Wilson, Dennis C Liotta
The rationale for the structural and mechanistic basis of a tetrahydroisoquinoline (THIQ) based series of CXCR4 antagonists is presented. Using the previously reported crystal structures which reveal two distinct binding sites of CXCR4 defined as the small molecule (IT1t or minor) binding pocket and peptide (CVX15 or major) binding pocket, we hypothesized our THIQ small molecule series could bind like either molecule in these respective receptor configurations (IT1t versus CVX15 based poses). To this end, a thorough investigation was performed through a combination of receptor mutation studies, medicinal chemistry, biological testing, conformational analysis, and flexible docking...
January 10, 2019: ACS Medicinal Chemistry Letters
Lisa Vieider, Erik Romp, Veronika Temml, Jana Fischer, Christian Kretzer, Martin Schoenthaler, Abdulla Taha, Victor Hernández-Olmos, Sonja Sturm, Daniela Schuster, Oliver Werz, Ulrike Garscha, Barbara Matuszczak
A series of derivatives of the potent dual soluble epoxide hydrolase (sEH)/5-lipoxygenase-activating protein (FLAP) inhibitor diflapolin was designed, synthesized, and characterized by 1 H NMR, 13 C NMR, and elemental analysis. These novel compounds were biologically evaluated for their inhibitory activity against sEH and FLAP. Molecular modeling tools were applied to analyze structure-activity relationships (SAR) on both targets. Results show that even small modifications on the lead compound diflapolin markedly influence the inhibitory potential, especially on FLAP, suggesting very narrow SAR...
January 10, 2019: ACS Medicinal Chemistry Letters
Naoko Ichiishi, Keith P Moore, Anne Mai Wassermann, Scott E Wolkenberg, Shane W Krska
Access to high quality photoaffinity probe molecules is often constrained by synthetic limitations related to diazirine installation. A survey of recently published photoaffinity probe syntheses identified the Suzuki-Miyaura (S-M) coupling reaction, ubiquitous in drug discovery, as being underutilized to incorporate diazirines. To test whether advances in modern cross-coupling catalysis might enable efficient S-M couplings tolerant of the diazirine moiety, a fragment-based screening approach was employed. A model S-M coupling reaction was screened under various conditions in the presence of an aromatic diazirine fragment...
January 10, 2019: ACS Medicinal Chemistry Letters
Mehmet Kahraman, Steven P Govek, Johnny Y Nagasawa, Andiliy Lai, Celine Bonnefous, Karensa Douglas, John Sensintaffar, Nhin Liu, KyoungJin Lee, Anna Aparicio, Josh Kaufman, Jing Qian, Gang Shao, Rene Prudente, James D Joseph, Beatrice Darimont, Daniel Brigham, Richard Heyman, Peter J Rix, Jeffrey H Hager, Nicholas D Smith
The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene 17ha . In a tamoxifen-resistant breast cancer xenograft model, 17ha (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, 5a (ER-α degradation efficacy = 91%) had inferior activity...
January 10, 2019: ACS Medicinal Chemistry Letters
Le Van Huy, Chiaki Tanaka, Takashi Imai, Sho Yamasaki, Tomofumi Miyamoto
Fifteen glycosyl-oxystearates were synthesized by Crich's 4,6-benzylidene and Köening-Knorr strategies. Assessment of structure-activity relationships using macrophage-inducible C-type lectin (Mincle) receptor cells expressing nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) revealed that four dimannopyranosyl-oxystearate analogues were Mincle agonists and that 12- O -(2- O -α-d-mannopyranosyl)-α-d-mannopyranosyl-oxystearate was as an activator of both mouse and human Mincle.
January 10, 2019: ACS Medicinal Chemistry Letters
Zhuo Wu, Xiao-Lu Bao, Wei-Bo Zhu, Yan-Hui Wang, Nguyen Thi Phuong Anh, Xiao-Feng Wu, Yi-Jia Yan, Zhi-Long Chen
A series of new angiotensin II receptor 1 antagonists were prepared. They displayed nanomolar affinity to AT1 receptor and could decrease blood pressure efficiently in spontaneously hypertensive rats. Among them, compounds 1b and 2b could reduce the blood pressure with more or equal potency compared to Losartan. So, compounds 1b and 2b could be considered as potential antihypertension drug candidates.
January 10, 2019: ACS Medicinal Chemistry Letters
Cyril Fersing, Louise Basmaciyan, Clotilde Boudot, Julien Pedron, Sébastien Hutter, Anita Cohen, Caroline Castera-Ducros, Nicolas Primas, Michèle Laget, Magali Casanova, Sandra Bourgeade-Delmas, Mélanie Piednoel, Alix Sournia-Saquet, Valère Belle Mbou, Bertrand Courtioux, Élisa Boutet-Robinet, Marc Since, Rachel Milne, Susan Wyllie, Alan H Fairlamb, Alexis Valentin, Pascal Rathelot, Pierre Verhaeghe, Patrice Vanelle, Nadine Azas
Twenty nine original 3-nitroimidazo[1,2- a ]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 μM) alongside good antileishmanial activities (IC50 = 1-2.1 μM) against L. donovani , L. infantum , and L. major ; and good antitrypanosomal activities (IC50 = 1.3-2.2 μM) against T. brucei brucei and T...
January 10, 2019: ACS Medicinal Chemistry Letters
Lei Wang, Guan-Hua Qiao, Hai-Ning Hu, Zhao-Bing Gao, Fa-Jun Nan
Recent research suggests that KCNQ isoforms, particularly the KCNQ4 and KCNQ5 subtypes expressed in smooth muscle cells, are involved in both establishing and maintaining resting membrane potentials and regulating smooth muscle contractility. Retigabine (RTG) is a first-in-class antiepileptic drug that potentiates neuronal KCNQ potassium channels, but poor subtype selectivity limits its further application as a pharmacological tool. In this study, we improved the subtype specificity of retigabine by altering the N-1/3 substituents and discovered several compounds that show better selectivity for KCNQ4 and KCNQ5 channels...
January 10, 2019: ACS Medicinal Chemistry Letters
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