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ACS Medicinal Chemistry Letters

Weijing Cai, Qi-Yin Chen, Long H Dang, Hendrik Luesch
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00192.].
December 14, 2017: ACS Medicinal Chemistry Letters
Marion Lanier, Jason Pickens, Simone V Bigi, Erica L Bradshaw-Pierce, Alison Chambers, Zacharia S Cheruvallath, Derek Cole, Douglas R Dougan, Jacques Ermolieff, Tony Gibson, Petro Halkowycz, Aki Hirokawa, Anthony Ivetac, Christopher McBride, Joanne Miura, Evan Nunez, Mark Sabat, John Tyhonas, Haixia Wang, Xiaolun Wang, Steve Swann
[This corrects the article DOI: 10.1021/acsmedchemlett.6b00481.].
December 14, 2017: ACS Medicinal Chemistry Letters
Dong-Oh Yoon, Xiaodi Zhao, Dohyun Son, Jung Tae Han, Jaesook Yun, Dongyun Shin, Hyun-Ju Park
G-protein coupled receptor 40 (GPR40) has been considered to be an attractive drug target for the treatment of type 2 diabetes because of its role in free fatty acids-mediated enhancement of glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. A series of indole-5-propanoic acid compounds were synthesized, and their GPR40 agonistic activities were evaluated by nuclear factor of activated T-cells reporter assay and GSIS assay in the MIN-6 insulinoma cells. Three compounds, 8h (EC50 = 58.6 nM), 8i (EC50 = 37...
December 14, 2017: ACS Medicinal Chemistry Letters
Ying-Ying Chen, Lavanya Gopala, Rammohan R Yadav Bheemanaboina, Han-Bo Liu, Yu Cheng, Rong-Xia Geng, Cheng-He Zhou
A series of novel naphthalimide aminothiazoles were developed for the first time and evaluated for their antimicrobial activity. Some prepared compounds possessed good inhibitory activity against the tested bacteria and fungi. Noticeably, the piperazine derivative 4d displayed superior antibacterial activity against MRSA and Escherichia coli with MIC values of 4 and 8 μg/mL, respectively, to reference drugs. The most active compound 4d showed low toxicity against mammalian cells with no obvious triggering of the development of bacterial resistance, and it also possessed rapid bactericidal efficacy and efficient membrane permeability...
December 14, 2017: ACS Medicinal Chemistry Letters
Carson W Reed, Kevin M McGowan, Paul K Spearing, Branden J Stansley, Hanna F Roenfanz, Darren W Engers, Alice L Rodriguez, Eileen M Engelberg, Vincent B Luscombe, Matthew T Loch, Daniel H Remke, Jerri M Rook, Anna L Blobaum, P Jeffrey Conn, Colleen M Niswender, Craig W Lindsley
Herein, we report the structure-activity relationships within a series of mGlu7 NAMs based on an N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamide core with excellent CNS penetration (Kp 1.9-5.8 and Kp,uu 0.4-1.4). Analogues in this series displayed steep SAR. Of these, VU6010608 (11a) emerged with robust efficacy in blocking high frequency stimulated long-term potentiation in electrophysiology studies.
December 14, 2017: ACS Medicinal Chemistry Letters
Yosuke Ogoshi, Takuya Matsui, Ikuo Mitani, Masahiro Yokota, Masakazu Terashita, Dai Motoda, Kazuhito Ueyama, Takahiro Hotta, Takashi Ito, Yasunori Hase, Kenji Fukui, Katsuya Deai, Hiromi Yoshiuchi, Soichiro Ito, Hiroyuki Abe
Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π-π stacking interactions with Tyr310...
December 14, 2017: ACS Medicinal Chemistry Letters
Alessio Nocentini, Silvia Bua, Carrie L Lomelino, Robert McKenna, Marta Menicatti, Gianluca Bartolucci, Barbara Tenci, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Paola Gratteri, Claudiu T Supuran
Incorporation of the purine/pyrimidine moieties as tails to classical benzenesulfonamide scaffolds afforded two series of human (h) carbonic anhydrase (CA, EC inhibitors. The compounds were designed according to the molecular hybridization approach, in order to modulate the interaction with different CA isozymes and exploit the antitumor effect of uracil and adenine derivatives in parallel and synergic mode to the inhibition of the tumor-associated hCA IX. The sulfonamides were investigated as inhibitors of four isoforms, cytosolic hCA I/II and transmembrane hCA IV/IX...
December 14, 2017: ACS Medicinal Chemistry Letters
Sangdon Han, Lars Thoresen, Jae-Kyu Jung, Xiuwen Zhu, Jayant Thatte, Michelle Solomon, Ibragim Gaidarov, David J Unett, Woo Hyun Yoon, Jeremy Barden, Abu Sadeque, Amin Usmani, Chuan Chen, Graeme Semple, Andrew J Grottick, Hussein Al-Shamma, Ronald Christopher, Robert M Jones
The discovery of a novel, selective and fully efficacious CB2 agonist with satisfactory pharmacokinetic and pharmaceutical properties is described. Compound 6 was efficacious in a rat model of osteoarthritis pain following oral administration and, in contrast to morphine, maintained its analgesic effect throughout a 5-day subchronic treatment paradigm. These data were consistent with our hypothesis that full agonist efficacy is required for efficient internalization and recycling of the CB2 receptor to avoid tachyphylaxis...
December 14, 2017: ACS Medicinal Chemistry Letters
Nada Abla, Sridevi Bashyam, Susan A Charman, Béatrice Greco, Philip Hewitt, Maria Belén Jiménez-Díaz, Kasiram Katneni, Holger Kubas, Didier Picard, Yuvaraj Sambandan, Laura Sanz, Dennis Smith, Tai Wang, Paul Willis, Sergio Wittlin, Thomas Spangenberg
With ∼429,000 deaths in 2016, malaria remains a major infectious disease where the need to treat the fever symptoms, but also to provide relevant post-treatment prophylaxis, is of major importance. An azepanylcarbazole amino alcohol is disclosed with a long- and fast-acting in vivo antiplasmodial efficacy and meets numerous attributes of a desired post-treatment chemoprophylactic antimalarial agent. The synthesis, the parasitological characterization, and the animal pharmacokinetics and pharmacodynamics of this compound are presented along with a proposed target...
December 14, 2017: ACS Medicinal Chemistry Letters
Phillip P Sharp, Jean-Marc Garnier, Tamas Hatfaludi, Zhen Xu, David Segal, Kate E Jarman, Hélène Jousset, Alexandra Garnham, John T Feutrill, Anthony Cuzzupe, Peter Hall, Scott Taylor, Carl R Walkley, Dean Tyler, Mark A Dawson, Peter Czabotar, Andrew F Wilks, Stefan Glaser, David C S Huang, Christopher J Burns
A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c-MYC expression...
December 14, 2017: ACS Medicinal Chemistry Letters
Christopher J Bungard, Peter D Williams, Jurgen Schulz, Catherine M Wiscount, M Katharine Holloway, H Marie Loughran, Jesse J Manikowski, Hua-Poo Su, David J Bennett, Lehua Chang, Xin-Jie Chu, Alejandro Crespo, Michael P Dwyer, Kartik Keertikar, Gregori J Morriello, Andrew W Stamford, Sherman T Waddell, Bin Zhong, Bin Hu, Tao Ji, Tracy L Diamond, Carolyn Bahnck-Teets, Steven S Carroll, John F Fay, Xu Min, William Morris, Jeanine E Ballard, Michael D Miller, John A McCauley
Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718.
December 14, 2017: ACS Medicinal Chemistry Letters
Thomas K Dawson, Pawel Dziedzic, Michael J Robertson, José A Cisneros, Stefan G Krimmer, Ana S Newton, Julian Tirado-Rives, William L Jorgensen
Coordination of the ammonium group of Lys32 in the active site of human macrophage migration inhibitory factor (MIF) using a 1,7-naphthyridin-8-one instead of a quinoline is investigated. Both gas- and aqueous-phase DFT calculations for model systems indicate potential benefits for the added hydrogen bond with the lactam carbonyl group, while FEP results are neutral. Three crystal structures are reported for complexes of MIF with 3a, 4a, and 4b, which show that the desired hydrogen bond is formed with O-N distances of 2...
December 14, 2017: ACS Medicinal Chemistry Letters
Masahiko Terakado, Hidehiro Suzuki, Kazuya Hashimura, Motoyuki Tanaka, Hideyuki Ueda, Keisuke Hirai, Masaki Asada, Masahiro Ikura, Naoki Matsunaga, Hiroshi Saga, Koji Shinozaki, Naoko Karakawa, Yuka Takada, Masashi Minami, Hiromu Egashira, Yoshihiro Sugiura, Masanori Yamada, Shinji Nakade, Yoshikazu Takaoka
Scaffold hopping from the amide group of lead compound ONO-7300243 (1) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA1) antagonist 4. Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to pyrrole and an indane moiety afforded an optimized compound ONO-0300302 (19). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, p...
December 14, 2017: ACS Medicinal Chemistry Letters
Andrew M Thompson, Muriel Bonnet, Ho H Lee, Scott G Franzblau, Baojie Wan, George S Wong, Christopher B Cooper, William A Denny
A published study of structural features associated with the aerobic and anaerobic activities of 4- and 5-nitroimidazoles had found that the 3-nitro isomer of pretomanid, 8, displayed interesting potencies, including against nitroreductase mutant Mycobacterium tuberculosis. However, recent nuclear magnetic resonance analyses of two trace byproducts, isolated from early process optimization studies toward a large-scale synthesis of pretomanid, raised structural assignment queries, particularly for 8, stimulating further investigation...
December 14, 2017: ACS Medicinal Chemistry Letters
Wenting Zhang, Wei Fan, Zhengyuan Zhou, Jered Garrison
Tumor hypoxia has been widely explored over the years as a diagnostic and therapeutic marker. Herein, we synthesized an alkyne functionalized version of evofosfamide, a hypoxia-selective prodrug. The purpose of this effort was to investigate if this novel 2-nitroimidazole phosphoramide nitrogen mustard (2-NIPAM) retained hypoxia selectivity and could be utilized in radiopharmaceutical development to significantly increase retention of conjugated agents in hypoxic cells. 2-NIPAM demonstrated good hypoxia selectivity with a 62- and 225-fold increase in cytotoxicity toward PC-3 and DU145 human prostate cancer cell lines, respectively, under hypoxic conditions...
December 14, 2017: ACS Medicinal Chemistry Letters
Lewis D Turner, Abbey J Summers, Laura O Johnson, Margaret A Knowles, Colin W G Fishwick
Structure-based drug design (SBDD) has become a powerful tool utilized by medicinal chemists to rationally guide the drug discovery process. Herein, we describe the use of SPROUT, a de novo-based program, to identify an indazole-based pharmacophore for the inhibition of fibroblast growth factor receptor (FGFR) kinases, which are validated targets for cancer therapy. Hit identification using SPROUT yielded 6-phenylindole as a small fragment predicted to bind to FGFR1. With the aid of docking models, several modifications to the indole were made to optimize the fragment to an indazole-containing pharmacophore, leading to a library of compounds containing 23 derivatives...
December 14, 2017: ACS Medicinal Chemistry Letters
Spencer D Wood, Wayne Grant, Isabel Adrados, Jun Yong Choi, James M Alburger, Derek R Duckett, William R Roush
We present the outcome of an in silico high throughput screen (HTS) and optimization of a small molecule Unc-51-Like Kinase 1 (ULK1) inhibitor hit, SR-17398, with an indazole core. Docking studies guided design efforts that led to inhibitors with increased activity vs ULK1 (IC50 < 50 nM). The most advanced molecules in this inhibitor series (3a and 3g) hold promise for further development into selective ULK1 molecular probes to interrogate the biology of ULK1 and to assess whether selectively targeting autophagy is an effective anticancer strategy...
December 14, 2017: ACS Medicinal Chemistry Letters
Christian A Kuttruff, Marco Ferrara, Tom Bretschneider, Stefan Hoerer, Sandra Handschuh, Bernd Nosse, Helmut Romig, Paul Nicklin, Gerald J Roth
In an effort to find new therapeutic interventions addressing the unmet medical need of patients with idiopathic pulmonary fibrosis, we initiated a program to identify new autotaxin (ATX) inhibitors. Starting from a recently published compound (PF-8380), we identified several highly potent ATX inhibitors with improved pharmacokinetic and safety profiles. Further optimization efforts resulted in the identification of a single-digit nanomolar lead compound (BI-2545) that shows substantial lowering of LPA in vivo and is therefore considered a valuable tool for further studies...
December 14, 2017: ACS Medicinal Chemistry Letters
Hualing Xiao, Peng Li, Xiaolin Li, Haiying He, Jianhua Wang, Fengxun Guo, Jiliang Zhang, Luxia Wei, Hongmei Zhang, Yueyuan Shi, Lijuan Hou, Liang Shen, Zhengxia Chen, Chunyan Du, Shouliang Fu, Pengtao Zhang, Fei Hao, Ping Wang, Deming Xu, Wei Liang, Xin Tian, Aiming Zhang, Xingdong Cheng, Ling Yang, Xiangjian Wang, Xiquan Zhang, Jian Li, Shuhui Chen
Farnesoid X receptor (FXR) has become a particularly attractive target for the discovery of drugs for the treatment of liver and metabolic diseases. Obeticholic acid (INT-747), a FXR agonist, has advanced into clinical phase III trials in patients with nonalcoholic steatohepatitis (NASH), but adverse effects (e.g., pruritus, LDL increase) were observed. Pruritus might be induced by Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1), and there are chances to develop FXR agonists with higher selectivity over TGR5...
December 14, 2017: ACS Medicinal Chemistry Letters
Abir Bhattacharjee, Antara Sinha, Kiira Ratia, Liang Yin, Loruhama Delgado-Rivera, Pavel A Petukhov, Gregory R J Thatcher, Duncan J Wardrop
Hydrogen sulfide is produced from l-cysteine by the action of both cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) and increasingly has been found to play a profound regulatory role in a range of physiological processes. Mounting evidence suggests that upregulation of hydrogen sulfide biosynthesis occurs in several disease states, including rheumatoid arthritis, hypertension, ischemic injury, and sleep-disordered breathing. In addition to being critical tools in our understanding of hydrogen sulfide biology, inhibitors of CSE hold therapeutic potential for the treatment of diseases in which increased levels of this gasotransmitter play a role...
December 14, 2017: ACS Medicinal Chemistry Letters
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