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ACS Medicinal Chemistry Letters

Ikuo Miyahisa, Hideo Suzuki, Atsushi Mizukami, Yukiya Tanaka, Midori Ono, Mark S Hixon, Junji Matsui
Delta-5 desaturase (D5D) catalyzes the conversion from dihomo-gamma linoleic acid (DGLA) to arachidonic acid (AA). DGLA and AA are common precursors of anti- and pro-inflammatory eicosanoids, respectively, making D5D an attractive drug target for inflammatory-related diseases. Despite several reports on D5D inhibitors, their biochemical mechanisms of action (MOAs) remain poorly understood, primarily due to the difficulty in performing quantitative enzymatic analysis. Herein, we report a radioligand binding assay to overcome this challenge and characterized T-3364366, a thienopyrimidinone D5D inhibitor, by use of the assay...
September 8, 2016: ACS Medicinal Chemistry Letters
Catherine A Evans, Tao Liu, André Lescarbeau, Somarajan J Nair, Louis Grenier, Johan A Pradeilles, Quentin Glenadel, Thomas Tibbitts, Ann M Rowley, Jonathan P DiNitto, Erin E Brophy, Erin L O'Hearn, Janid A Ali, David G Winkler, Stanley I Goldstein, Patrick O'Hearn, Christian M Martin, Jennifer G Hoyt, John R Soglia, Culver Cheung, Melissa M Pink, Jennifer L Proctor, Vito J Palombella, Martin R Tremblay, Alfredo C Castro
Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.
September 8, 2016: ACS Medicinal Chemistry Letters
Spencer B Jones, Lance A Pfeifer, Thomas J Bleisch, Thomas J Beauchamp, Jim D Durbin, V Joseph Klimkowski, Norman E Hughes, Christopher J Rito, Yen Dao, Joseph M Gruber, Hai Bui, Mark G Chambers, Srinivasan Chandrasekhar, Chaohua Lin, Denis J McCann, Daniel R Mudra, Jennifer L Oskins, Craig A Swearingen, Kannan Thirunavukkarasu, Bryan H Norman
In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship...
September 8, 2016: ACS Medicinal Chemistry Letters
Yikai Wang, Jean-Yves Wach, Patrick Sheehan, Cheng Zhong, Chenyang Zhan, Richard Harris, Steven C Almo, Joshua Bishop, Stephen J Haggarty, Alexander Ramek, Kayla N Berry, Conor O'Herin, Angela N Koehler, Alvin W Hung, Damian W Young
Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3β, allow the systematic synthesis of related fragment analogues to explore fragment-level structure-activity relationship, and finally lead to the synthesis of a more potent compound.
September 8, 2016: ACS Medicinal Chemistry Letters
Haya Jamali, Hasan A Khan, Caroline C Tjin, Jonathan A Ellman
The protein arginine deiminases (PADs) catalyze the post-translational deimination of arginine side chains. Multiple PAD isozymes have been characterized, and abnormal PAD activity has been associated with several human disease states. PAD3 has been characterized as a modulator of cell growth via apoptosis inducing factor and has been implicated in the neurodegenerative response to spinal cord injury. Here, we describe the design, synthesis, and evaluation of conformationally constrained versions of the potent and selective PAD3 inhibitor 2...
September 8, 2016: ACS Medicinal Chemistry Letters
Erika J Olson, Bernhard C Lechtenberg, Chunxia Zhao, Elena Rubio de la Torre, Ilaria Lamberto, Stefan J Riedl, Philip E Dawson, Elena B Pasquale
EphA4 is a receptor tyrosine kinase with a critical role in repulsive axon guidance and synaptic function. However, aberrant EphA4 activity can inhibit neural repair after injury and exacerbate neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's. We previously identified the cyclic peptide APY-d2 (APYCVYRβASWSC-nh2, containing a disulfide bond) as a potent and selective EphA4 antagonist. However, APY-d2 lacks sufficient plasma stability to be useful for EphA4 inhibition in vivo through peripheral administration...
September 8, 2016: ACS Medicinal Chemistry Letters
Meng-Chen Lu, Shi-Jie Tan, Jian-Ai Ji, Zhi-Yun Chen, Zhen-Wei Yuan, Qi-Dong You, Zheng-Yu Jiang
Directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as an attractive way to activate Nrf2, and Keap1-Nrf2 PPI inhibitors have been proposed as potential agents to relieve inflammatory and oxidative stress diseases. In this work, we investigated the diacetic moiety around the potent Keap1-Nrf2 PPI inhibitor DDO1018 (2), which was reported by our group previously. Exploration of bioisosteric replacements afforded the ditetrazole analog 7, which maintains the potent PPI inhibition activity (IC50 = 15...
September 8, 2016: ACS Medicinal Chemistry Letters
Heather J Finlay, James A Johnson, John L Lloyd, Ji Jiang, James Neels, Prashantha Gunaga, Abhisek Banerjee, Naveen Dhondi, Anjaneya Chimalakonda, Sandhya Mandlekar, Mary Lee Conder, Harinath Sale, Dezhi Xing, Paul Levesque, Ruth R Wexler
A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.
September 8, 2016: ACS Medicinal Chemistry Letters
Xiang-Guo Li, Cecilia Hagert, Riikka Siitonen, Helena Virtanen, Outi Sareila, Heidi Liljenbäck, Jouni Tuisku, Juhani Knuuti, Jörgen Bergman, Rikard Holmdahl, Anne Roivainen
Recently mannan from Saccharomyces cerevisiae has been shown to be able to induce psoriasis and psoriatic arthritis in mice, and the phenotypes resemble the corresponding human diseases. To investigate the pathological processes, we set out to label mannan with fluorine-18 ((18)F) and study the (18)F-labeled mannan in vitro and in vivo with positron emission tomography (PET). Accordingly, mannan has been transformed into (18)F-fluoromannan with (18)F-bicyclo[6.1.0]nonyne. In mouse aorta, the binding of [(18)F]fluoromannan to the atherosclerotic lesions was clearly visualized and was significantly higher compared to blocking assays (P < 0...
September 8, 2016: ACS Medicinal Chemistry Letters
Benjamin Blass
No abstract text is available yet for this article.
September 8, 2016: ACS Medicinal Chemistry Letters
Gerard Rosse
No abstract text is available yet for this article.
September 8, 2016: ACS Medicinal Chemistry Letters
Dong Guo, Laura H Heitman, Adriaan P IJzerman
In the past decade drug research community has started to appreciate the indispensable role of ligand-receptor binding kinetics (BK) in drug discovery. Next to the classical equilibrium-based drug evaluation process with affinity and potency values as outcomes, kinetic investigation of the ligand-receptor interaction can aid compound triage in the hit-to-lead campaign and provide additional information to understand the molecular mechanism of drug action. Translational models incorporating BK are emerging as well, which represent powerful tools for the prediction of in vivo effects...
September 8, 2016: ACS Medicinal Chemistry Letters
Jennifer E Sager, John R Choiniere, Justine Chang, Alyssa Stephenson-Famy, Wendel L Nelson, Nina Isoherranen
Bupropion is a widely used antidepressant and the recommended CYP2B6 probe drug. However, current understanding of bupropion elimination pathways is limited. Bupropion has three active circulating metabolites, OH-bupropion, threohydrobupropion, and erythrohydrobupropion, but together with bupropion these metabolites and their conjugates in urine represent only 23% of the dose, and the majority of the elimination pathways of bupropion result in uncharacterized metabolites. The aim of this study was to determine the structures of the uncharacterized bupropion metabolites using human clinical samples and in vitro incubations...
August 11, 2016: ACS Medicinal Chemistry Letters
Suman Ghosh, Yang Liu, Gaurav Garg, Mercy Anyika, Nolan T McPherson, Jiacheng Ma, Rick T Dobrowsky, Brian S J Blagg
Novobiocin is a natural product that binds the Hsp90 C-terminus and manifests Hsp90 inhibitory activity. Structural investigations on novobiocin led to the development of both anti-cancer and neuroprotective agents. The varied pharmacological activity manifested by these novobiocin analogs prompted the investigation of structure-function studies to identify these contradictory effects, which revealed that modifications to the amide side chain produce either anti-cancer or neuroprotective activity. Compounds that exhibit neuroprotective activity contain a short alkyl or cycloalkyl amide side chain...
August 11, 2016: ACS Medicinal Chemistry Letters
Tianming Yang, Wai Har Ng, Huan Chen, Kamon Chomchopbun, The Hung Huynh, Mei Lin Go, Oi Lian Kon
Lung cancer cells harboring activating EGFR mutations acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) by activating several bypass mechanisms, including MET amplification and overexpression. We show that a significant proportion of activated MET protein in EGFR TKI-resistant HCC827 lung cancer cells resides within the mitochondria. Targeting the total complement of MET in the plasma membrane and mitochondria should render these cells more susceptible to cell death and hence provide a means of circumventing drug resistance...
August 11, 2016: ACS Medicinal Chemistry Letters
Zongxing Qiu, Bernd Kuhn, Johannes Aebi, Xianfeng Lin, Haiyuan Ding, Zheng Zhou, Zhiheng Xu, Danqing Xu, Li Han, Cheng Liu, Hongxia Qiu, Yuxia Zhang, Wolfgang Haap, Claus Riemer, Martin Stahl, Ning Qin, Hong C Shen, Guozhi Tang
ATG4B or autophagin-1 is a cysteine protease that cleaves ATG8 family proteins. ATG4B plays essential roles in the autophagosome formation and the autophagy pathway. Herein we disclose the design and structural modifications of a series of fluoromethylketone (FMK)-based peptidomimetics as highly potent ATG4B inhibitors. Their structure-activity relationship (SAR) and protease selectivity are also discussed.
August 11, 2016: ACS Medicinal Chemistry Letters
Lee D Fader, Murray Bailey, Eric Beaulieu, François Bilodeau, Pierre Bonneau, Yves Bousquet, Rebekah J Carson, Catherine Chabot, René Coulombe, Jianmin Duan, Craig Fenwick, Michel Garneau, Ted Halmos, Araz Jakalian, Clint James, Stephen H Kawai, Serge Landry, Steven R LaPlante, Stephen W Mason, Sebastien Morin, Nathalie Rioux, Bruno Simoneau, Simon Surprenant, Bounkham Thavonekham, Carl Thibeault, Thao Trinh, Youla Tsantrizos, Jennifer Tsoung, Christiane Yoakim, Dominik Wernic
Optimization of pyridine-based noncatalytic site integrase inhibitors (NCINIs) based on compound 2 has led to the discovery of molecules capable of inhibiting virus harboring N124 variants of HIV integrase (IN) while maintaining minimal contribution of enterohepatic recirculation to clearance in rat. Structure-activity relationships at the C6 position established chemical space where the extent of enterohepatic recirculation in the rat is minimized. Desymmetrization of the C4 substituent allowed for potency optimization against virus having the N124 variant of integrase...
August 11, 2016: ACS Medicinal Chemistry Letters
James K Johnson, Erin M Skoda, Jianhua Zhou, Erica Parrinello, Dan Wang, Katherine O'Malley, Benjamin R Eyer, Mustafa Kazancioglu, Kurtis Eisermann, Paul A Johnston, Joel B Nelson, Zhou Wang, Peter Wipf
After a high-throughput screening campaign identified thioether 1 as an antagonist of the nuclear androgen receptor, a zone model was developed for structure-activity relationship (SAR) purposes and analogues were synthesized and evaluated in a cell-based luciferase assay. A novel thioether isostere, cyclopropane (1S,2R)-27, showed the desired increased potency and structural properties (stereospecific SAR response, absence of a readily oxidized sulfur atom, low molecular weight, reduced number of flexible bonds and polar surface area, and drug-likeness score) in the prostate-specific antigen luciferase assay in C4-2-PSA-rl cells to qualify as a new lead structure for prostate cancer drug development...
August 11, 2016: ACS Medicinal Chemistry Letters
Rachit Shah, Alexander Strom, Andrew Zhou, Kimberly M Maize, Barry C Finzel, Carston R Wagner
Hint1 has recently emerged to be an important target of interest due to its involvement in the regulation of a broad range of CNS functions including opioid signaling, tolerance, neuropathic pain, and nicotine dependence. A series of inhibitors were rationally designed, synthesized, and tested for their inhibitory activity against hHint1 using isothermal titration calorimetry (ITC). The studies resulted in the development of the first small-molecule inhibitors of hHint1 with submicromolar binding affinities...
August 11, 2016: ACS Medicinal Chemistry Letters
Kshitij Verma, Tianzhu Zang, Nehal Gupta, Trevor M Penning, Paul C Trippier
We report the design, synthesis, and evaluation of potent and selective inhibitors of aldo-keto reductase 1C3 (AKR1C3), an important enzyme in the regulatory pathway controlling proliferation, differentiation, and apoptosis in myeloid cells. Combination treatment with the nontoxic AKR1C3 inhibitors and etoposide or daunorubicin in acute myeloid leukemia cell lines, elicits a potent adjuvant effect, potentiating the cytotoxicity of etoposide by up to 6.25-fold and the cytotoxicity of daunorubicin by >10-fold...
August 11, 2016: ACS Medicinal Chemistry Letters
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