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ACS Medicinal Chemistry Letters

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https://www.readbyqxmd.com/read/28105289/development-of-4-heteroarylamino-1-azaspiro-oxazole-5-3-bicyclo-2-2-2-octanes-as-%C3%AE-7-nicotinic-receptor-agonists
#1
Matthew D Hill, Haiquan Fang, H Dalton King, Christiana I Iwuagwu, Ivar M McDonald, James Cook, F Christopher Zusi, Robert A Mate, Ronald J Knox, Debra Post-Munson, Amy Easton, Regina Miller, Kimberley Lentz, Wendy Clarke, Yulia Benitex, Nicholas Lodge, Robert Zaczek, Rex Denton, Daniel Morgan, Linda Bristow, John E Macor, Richard Olson
We describe the synthesis of quinuclidine-containing spiroimidates and their utility as α7 nicotinic acetylcholine receptor (nAChR) partial agonists. A convergent synthetic route allowed for rapid SAR investigation and provided a diverse set of fused 6,5-heteroaryl analogs. Two potent and selective α7 nAChR partial agonists, (1'S,3'R,4'S)-N-(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine (20) and (1'S,3'R,4'S)-N-(7-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105288/discovery-of-spirocyclic-aldosterone-synthase-inhibitors-as-potential-treatments-for-resistant-hypertension
#2
Whitney L Petrilli, Scott B Hoyt, Clare London, Daniel McMasters, Andreas Verras, Mary Struthers, Doris Cully, Thomas Wisniewski, Ning Ren, Charlene Bopp, Andrea Sok, Qing Chen, Ying Li, Elaine Tung, Wei Tang, Gino Salituro, Ian Knemeyer, Bindhu Karanam, Joseph Clemas, Gaochao Zhou, Jack Gibson, Carrie Ann Shipley, Douglas J MacNeil, Ruth Duffy, James R Tata, Feroze Ujjainwalla, Amjad Ali, Yusheng Xiong
Herein we report the discovery and hit-to-lead optimization of a series of spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this series display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, and lead-like physical and pharmacokinetic properties.
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105287/systematic-study-of-effects-of-structural-modifications-on-the-aqueous-solubility-of-drug-like-molecules
#3
José A Cisneros, Michael J Robertson, Brandon Q Mercado, William L Jorgensen
Aqueous solubilities and activities have been measured for 17 members of the quinolinyltriazole series of inhibitors of human macrophage migration inhibitory factor (MIF). Systematic variation of a solvent-exposed substituent provided increases in solubility from 2 μg/mL for the parent compound 3a up to 867 μg/mL. The low solubility of 3a results from its near-planar structure and an intermolecular hydrogen bond, as revealed in a small-molecule X-ray structure. Removal of the hydrogen bond yields a 3-fold increase in solubility, but a 7-fold drop in activity...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105286/discovery-of-a-potent-selective-and-orally-available-pi3k%C3%AE-inhibitor-for-the-treatment-of-inflammatory-diseases
#4
Montse Erra, Joan Taltavull, Angelique Gréco, Francisco Javier Bernal, Juan Francisco Caturla, Jordi Gràcia, María Domínguez, Mar Sabaté, Stéphane Paris, Salomé Soria, Begoña Hernández, Clara Armengol, Judit Cabedo, Mónica Bravo, Elena Calama, Montserrat Miralpeix, Martin D Lehner
The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105285/structural-basis-for-the-effective-myostatin-inhibition-of-the-mouse-myostatin-prodomain-derived-minimum-peptide
#5
Tomo Asari, Kentaro Takayama, Akari Nakamura, Takahiro Shimada, Akihiro Taguchi, Yoshio Hayashi
Myostatin inhibition is one of the promising strategies for treating muscle atrophic disorders, including muscular dystrophy. It is well-known that the myostatin prodomain derived from the myostatin precursor acts as an inhibitor of mature myostatin. In our previous study, myostatin inhibitory minimum peptide 1 (WRQNTRYSRIEAIKIQILSKLRL-amide) was discovered from the mouse myostatin prodomain. In the present study, alanine scanning of 1 demonstrated that the key amino acid residues for the effective inhibitory activity are rodent-specific Tyr and C-terminal aliphatic residues, in addition to N-terminal Trp residue...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105284/discovery-of-novel-seven-membered-prostacyclin-analogues-as-potent-and-selective-prostaglandin-fp-and-ep3-dual-agonists
#6
Isamu Sugimoto, Tohru Kambe, Tomotaka Okino, Tetsuo Obitsu, Nobukazu Ohta, Taihei Nishiyama, Akihiro Kinoshita, Taku Fujimoto, Hiromu Egashira, Shinsaku Yamane, Satoshi Shuto, Kousuke Tani, Toru Maruyama
A novel series of prostaglandin analogues with a seven-membered ring scaffold was designed, synthesized, and evaluated for the functional activation of prostaglandin receptors to identify potent and subtype-selective FP and EP3 dual agonists. Starting from the prostacyclin derivative 5b, a nonselective agonist for prostaglandin receptors, replacement of the core structure with an octahydro-2H-cyclopenta[b]oxepine scaffold led to the discovery of the potent and selective FP and EP3 dual agonist 11b as a lead compound for the development of an antiglaucoma agent...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105283/rational-design-of-a-boron-modified-triphenylethylene-gll398-as-an-oral-selective-estrogen-receptor-downregulator
#7
Jiawang Liu, Shilong Zheng, Shanchun Guo, Changde Zhang, Qiu Zhong, Qiang Zhang, Peng Ma, Elena V Skripnikova, Melyssa R Bratton, Thomas E Wiese, Guangdi Wang
Development of orally bioavailable nonsteroidal selective estrogen receptor downregulators (SERDs) provides clinical opportunities for the long-term treatment and adjuvant therapy of breast cancer at all stages. We describe the design, synthesis, and identification of a boron-modified GW7604 derivative (GLL398, 9), a SERD candidate, in which a boronic acid functional group replaces the phenolic hydroxyl group of GW7604. Compound 9 strongly binds to ERα in a fluorescence resonance energy transfer binding assay (IC50 = 1...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105282/discovery-of-chromane-propionic-acid-analogues-as-selective-agonists-of-gpr120-with-in-vivo-activity-in-rodents
#8
Gregory L Adams, Francisco Velazquez, Charles Jayne, Unmesh Shah, Shouwu Miao, Eric R Ashley, Maria Madeira, Taro E Akiyama, Jerry Di Salvo, Takao Suzuki, Nengxue Wang, Quang Truong, Eric Gilbert, Dan Zhou, Andreas Verras, Melissa Kirkland, Michele Pachanski, Maryann Powles, Wu Yin, Feroze Ujjainwalla, Srikanth Venkatraman, Scott D Edmondson
GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A selective activator of GPR120 containing a chromane scaffold has been designed, synthesized, and evaluated in vivo. Results of these efforts suggest that chromane propionic acid 18 is a suitable tool molecule for further animal studies. Compound 18 is selective over the closely related target GPR40 (FFAR1), has a clean off-target profile, demonstrates suitable pharmacokinetic properties, and has been evaluated in wild-type/knockout GPR120 mouse oGTT studies...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105281/n-1-benzyl-3-5-dimethyl-1h-pyrazol-4-yl-benzamides-antiproliferative-activity-and-effects-on-mtorc1-and-autophagy
#9
Teng Ai, Rose Willett, Jessica Williams, Rui Ding, Daniel J Wilson, Jiashu Xie, Do-Hyung Kim, Rosa Puertollano, Liqiang Chen
Guided by antiproliferative activity in MIA PaCa-2 cells, we have performed preliminary structure-activity relationship studies on N-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides. Two selected compounds showed submicromolar antiproliferative activity and good metabolic stability. Both compounds reduced mTORC1 activity and increased autophagy at the basal level. In addition, they disrupted autophagic flux by interfering with mTORC1 reactivation and clearance of LC3-II under starvation/refeed conditions, as evidenced by accumulation of LC3-II and abnormal LC3 labeled punctae...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105280/glun2a-selective-pyridopyrimidinone-series-of-nmdar-positive-allosteric-modulators-with-an-improved-in-vivo-profile
#10
Elisia Villemure, Matthew Volgraf, Yu Jiang, Guosheng Wu, Cuong Q Ly, Po-Wai Yuen, Aijun Lu, Xifeng Luo, Mingcui Liu, Shun Zhang, Patrick J Lupardus, Heidi J A Wallweber, Bianca M Liederer, Gauri Deshmukh, Emile Plise, Suzanne Tay, Tzu-Ming Wang, Jesse E Hanson, David H Hackos, Kimberly Scearce-Levie, Jacob B Schwarz, Benjamin D Sellers
The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca(2+) and Na(+). NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recently, we have disclosed GNE-0723 (1), a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs. This work highlights the discovery of a related pyridopyrimidinone core with distinct structure-activity relationships, despite the structural similarity to GNE-0723...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105279/nanoconjugated-nap-as-a-potent-and-periphery-selective-mu-opioid-receptor-modulator-to-treat-opioid-induced-constipation
#11
Guoyan G Xu, Olga Yu Zolotarskaya, Dwight A Williams, Yunyun Yuan, Dana E Selley, William L Dewey, Hamid I Akbarali, Hu Yang, Yan Zhang
Opioids are the mainstay for cancer and noncancer pain management. However, their use is often associated with multiple adverse effects. Among them, the most common and persistent one is probably opioid-induced constipation (OIC). Periphery selective opioid antagonists may alleviate the symptoms of OIC without compromising the analgesic effects of opioids. Recently our laboratories have identified one novel lead compound, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)acetamido]morphinan (NAP), as a peripherally selective mu opioid receptor ligand carrying subnanomolar affinity to the mu opioid receptor and over 100-folds of selectivity over both the delta and kappa opioid receptors, with reasonable oral availability and half-life, and potential to treat OIC...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105278/hydrazone-linker-as-a-useful-tool-for-preparing-chimeric-peptide-nonpeptide-bifunctional-compounds
#12
Jolanta Dyniewicz, Piotr F J Lipiński, Piotr Kosson, Anna Leśniak, Marta Bochyńska-Czyż, Adriana Muchowska, Dirk Tourwé, Steven Ballet, Aleksandra Misicka, Andrzej W Lipkowski
The area of multitarget compounds, joining two pharmacophores within one molecule, is a vivid field of research in medicinal chemistry. Not only pharmacophoric elements are essential for the design and activity of such compounds, but the type and length of linkers used to connect them are also crucial. In the present contribution, we describe compound 1 in which a typical opioid peptide sequence is combined with a fragment characteristic for neurokinin-1 receptor (NK1R) antagonists through a hydrazone bridge...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105277/design-and-synthesis-of-novel-meta-linked-phenylglycine-macrocyclic-fviia-inhibitors
#13
Jeremy M Richter, Daniel L Cheney, J Alex Bates, Anzhi Wei, Joseph M Luettgen, Alan R Rendina, Timothy M Harper, Rangaraj Narayanan, Pancras C Wong, Dietmar Seiffert, Ruth R Wexler, E Scott Priestley
Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/FVIIa Ki was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability.
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105276/covalent-guanosine-mimetic-inhibitors-of-g12c-kras
#14
Yuan Xiong, Jia Lu, John Hunter, Lianbo Li, David Scott, Hwan Geun Choi, Sang Min Lim, Anuj Manandhar, Sudershan Gondi, Taebo Sim, Kenneth D Westover, Nathanael S Gray
Ras proteins are members of a large family of GTPase enzymes that are commonly mutated in cancer where they act as dominant oncogenes. We previously developed an irreversible guanosine-derived inhibitor, SML-8-73-1, of mutant G12C RAS that forms a covalent bond with cysteine 12. Here we report exploration of the structure-activity relationships (SAR) of hydrolytically stable analogues of SML-8-73-1 as covalent G12C KRAS inhibitors. We report the discovery of difluoromethylene bisphosphonate analogues such as compound 11, which, despite exhibiting reduced efficiency as covalent G12C KRAS inhibitors, remove the liability of the hydrolytic instability of the diphosphate moiety present in SML-8-73-1 and provide the foundation for development of prodrugs to facilitate cellular uptake...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105275/2-hydroxypyridine-n-oxide-embedded-aurones-as-potent-human-tyrosinase-inhibitors
#15
Romain Haudecoeur, Marcello Carotti, Aurélie Gouron, Marc Maresca, Elina Buitrago, Renaud Hardré, Elisabetta Bergantino, Hélène Jamet, Catherine Belle, Marius Réglier, Luigi Bubacco, Ahcène Boumendjel
With the aim to develop effective and selective human tyrosinase inhibitors, we investigated aurone derivatives whose B-ring was replaced by a non-oxidizable 2-hydroxypyridine-N-oxide (HOPNO) moiety. These aurones were synthesized and evaluated as inhibitors of purified human tyrosinase. Excellent inhibition activity was revealed and rationalized by theoretical calculations. The aurone backbone was especially found to play a crucial role, as the HOPNO moiety alone provided very modest activity on human tyrosinase...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105274/design-synthesis-and-evaluation-of-novel-and-selective-g-protein-coupled-receptor-120-gpr120-spirocyclic-agonists
#16
Jason M Cox, Hong D Chu, Mariappan V Chelliah, John S Debenham, Keith Eagen, Ping Lan, Matthew Lombardo, Clare London, Michael A Plotkin, Unmesh Shah, Zhongxiang Sun, Henry M Vaccaro, Srikanth Venkatraman, Takao Suzuki, Nengxue Wang, Eric R Ashley, Alejandro Crespo, Maria Madeira, Dennis H Leung, Candice Alleyne, Aimie M Ogawa, Sarah Souza, Brande Thomas-Fowlkes, Jerry Di Salvo, Adam Weinglass, Melissa Kirkland, Michele Pachanski, Mary Ann Powles, Effie Tozzo, Taro E Akiyama, Feroze Ujjainwalla, James R Tata, Christopher J Sinz
Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist 14...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105273/investigation-of-a-bicyclo-1-1-1-pentane-as-a-phenyl-replacement-within-an-lppla2-inhibitor
#17
Nicholas D Measom, Kenneth D Down, David J Hirst, Craig Jamieson, Eric S Manas, Vipulkumar K Patel, Don O Somers
We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105272/novel-potentiators-for-vancomycin-in-the-treatment-of-biofilm-related-mrsa-infections-via-a-mix-and-match-approach
#18
Arno Vermote, Gilles Brackman, Martijn D P Risseeuw, Davie Cappoen, Paul Cos, Tom Coenye, Serge Van Calenbergh
A library of 52 hamamelitannin analogues was synthesized and investigated for its ability to potentiate the effect of vancomycin toward Staphylococcus aureus biofilms. Several compounds were found to effectively increase the susceptibility of staphylococcal biofilms toward this glycopeptide. The most active analogue identified in this study showed an EC50 value of 0.26 μM.
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105271/biological-evaluation-in-vitro-and-in-silico-of-azetidin-2-one-derivatives-as-potential-anticancer-agents
#19
Fabián E Olazaran, Gildardo Rivera, Alondra M Pérez-Vázquez, Cynthia M Morales-Reyes, Aldo Segura-Cabrera, Isaías Balderas-Rentería
Potential anticancer activity of 16 azetidin-2-one derivatives was evaluated showing that compound 6 [N-(p-methoxy-phenyl)-2-(p-methyl-phenyl)-3-phenoxy-azetidin-2-one] presented cytotoxic activity in SiHa cells and B16F10 cells. The caspase-3 assay in B16F10 cells displayed that azetidin-2-one derivatives induce apoptosis. Microarray and molecular analysis showed that compound 6 was involved on specific gene overexpression of cytoskeleton regulation and apoptosis due to the inhibition of some cell cycle genes...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28105270/1-2-4-triazolidine-3-thiones-as-narrow-spectrum-antibiotics-against-multidrug-resistant-acinetobacter-baumannii
#20
William M Huggins, Bradley M Minrovic, Brendan W Corey, Anna C Jacobs, Roberta J Melander, Roger D Sommer, Daniel V Zurawski, Christian Melander
With only two new classes of antibiotics developed in the last 40 years, novel antibiotics are desperately needed to combat the growing problem of multidrug-resistant and extensively drug resistant bacteria, particularly Gram-negative bacteria. Described in this letter is the synthesis and antibiotic activity of 1,2,4-triazolidine-3-thiones as narrow spectrum antibiotics. Optimization of the 1,2,4-triazolidine-3-thione scaffold identified a small molecule with potent antibiotic activity against multiple strains of multidrug-resistant and extensively drug-resistant Acinetobacter baumannii...
January 12, 2017: ACS Medicinal Chemistry Letters
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