共查询到20条相似文献,搜索用时 156 毫秒
1.
Upul K. Bandarage Alex M. Aronov Jingrong Cao Jon H. Come Kevin M. Cottrell Robert J. Davies Simon Giroux Marc Jacobs Sudipta Mahajan David Messersmith Cameron S. Moody Rebecca Swett Jinwang Xu 《ACS medicinal chemistry letters》2021,12(1):129
Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes that control a wide variety of cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. PI3Kγ plays a critical role in mediating leukocyte chemotaxis as well as mast cell degranulation, making it a potentially interesting target for autoimmune and inflammatory diseases. We previously disclosed a novel series of PI3Kγ inhibitors derived from a benzothiazole core. The truncation of the benzothiazole core led to the discovery of a structurally diverse alkynyl thiazole series which displayed high PI3Kγ potency and subtype selectivity. Further medicinal chemistry optimization of the alkynyl thiazole series led to identification of compounds such as 14 and 32, highly potent, subtype selective, and CNS penetrant PI3Kγ inhibitors. Compound 14 showed robust inhibition of PI3Kγ mediated neutrophil migration in vivo. 相似文献
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Shohei Miwa Masahiro Yokota Yoshifumi Ueyama Katsuya Maeda Yosuke Ogoshi Noriyoshi Seki Naoki Ogawa Jun Nishihata Akihiro Nomura Tsuyoshi Adachi Yuki Kitao Keisuke Nozawa Tomohiro Ishikawa Yutaka Ukaji Makoto Shiozaki 《ACS medicinal chemistry letters》2021,12(5):745
Historically, modulation of transforming growth factor β (TGF-β) signaling has been deemed a rational strategy to treat many disorders, though few successful examples have been reported to date. This difficulty could be partially attributed to the challenges of achieving good specificity over many closely related enzymes that are implicated in distinct phenotypes in organ development and in tissue homeostasis. Recently, fresolimumab and disitertide, two peptidic TGF-β blockers, demonstrated significant therapeutic effects toward human skin fibrosis. Therefore, the selective blockage of TGF-β signaling assures a viable treatment option for fibrotic skin disorders such as systemic sclerosis (SSc). In this report, we disclose selective TGF-β type II receptor (TGF-βRII) inhibitors that exhibited high functional selectivity in cell-based assays. The representative compound 29 attenuated collagen type I alpha 1 chain (COL1A1) expression in a mouse fibrosis model, which suggests that selective inhibition of TGF-βRII-dependent signaling could be a new treatment for fibrotic disorders. 相似文献
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Chunpu Li Sha-Sha Hu Lisheng Yang Min Wang Jian-Dong Long Bing Wang Haozhen Han Haoran Zhu Sen Zhao Jing-Gen Liu Dongxiang Liu Hong Liu 《ACS medicinal chemistry letters》2021,12(3):397
SIRT1, a member of the sirtuin family, catalyzes the deacetylation of proteins with the transformation of NAD+ into nicotinamide and 2′-O-acetyl-ADP-ribose. Selective SIRT1/2 inhibitors have potential application in the chemotherapy of colorectal carcinoma, prostate cancer, and myelogenous leukemia. Here we identified novel SIRT1 inhibitors with the scaffold of 5-benzylidene-2-phenyl-1,3-dioxane-4,6-dione. The most potent inhibitor 12n displayed an IC50 of 460 nM and a selectivity for SIRT1 over SIRT2, SIRT3, and SIRT5 of 113.5-, 254.3-, and 10.83-fold, respectively. It did not affect the activity of SIRT6. To elucidate the inhibitory mechanism, we determined the inhibition type of the inhibitor by enzyme kinetic analysis, showing that the inhibitor was competitive to the acetyl peptide and noncompetitive to NAD+. Further, the interaction of the inhibitor in SIRT1 was studied by using molecular docking, which was validated by the structure–activity relationship analysis of the inhibitors and the site-directed mutagenesis of SIRT1. Consistent with the in vitro assays, the inhibitors increased the acetylation level of p53 in a concentration-dependent manner in cells. 相似文献
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Mark S. Tichenor John J. M. Wiener Navin L. Rao Charlotte Pooley Deckhut J. Kent Barbay Kevin D. Kreutter Genesis M. Bacani Jianmei Wei Leon Chang Heather E. Murrey Weixue Wang Kay Ahn Michael Huber Elizabeth Rex Kevin J. Coe JieJun Wu Mark Seierstad Scott D. Bembenek Kristi A. Leonard Alec D. Lebsack Jennifer D. Venable James P. Edwards 《ACS medicinal chemistry letters》2021,12(5):782
Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound 27 irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound 27 is characterized by selectivity for BTK, potent in vivo BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model. 相似文献
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Agnete Viuff Stphane Salamone Joseph McLoughlin Janet E. Deane Henrik H. Jensen 《ACS medicinal chemistry letters》2021,12(1):56
Competitive inhibitors of galactocerebrosidase (GALC) could be candidates for pharmacological chaperone therapy of patients with Krabbe disease. The known and selective nortropane-type iminosugar galacto-noeurostegine has been found to competitively inhibit GALC with Ki = 7 μM at pH 4.6, which is 330-fold more potent than the analogous deoxynoeurostegine. It was shown through X-ray protein crystallography that galacto-noeurostegine binds to the active site of GALC in its bicyclic form. 相似文献
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MonikaA. Lewandowska-Goch Anna Kwiatkowska Teresa epek Kvin Ly Pauline Navals Hugo Gagnon Yves L. Dory Adam Prahl Robert Day 《ACS medicinal chemistry letters》2021,12(3):365
Furin plays an important role in various pathological states, especially in bacterial and viral infections. A detailed understanding of the structural requirements for inhibitors targeting this enzyme is crucial to develop new therapeutic strategies in infectious diseases, including an urgent unmet need for SARS-CoV-2 infection. Previously, we have identified a potent furin inhibitor, peptide Ac-RARRRKKRT-NH2 (CF1), based on the highly pathogenic avian influenza hemagglutinin. The goal of this study was to determine how its N-terminal part (the P8–P5 positions) affects its activity profile. To do so, the positional-scanning libraries of individual peptides modified at the selected positions with natural amino acids were generated. Subsequently, the best substitutions were combined together and/or replaced by unnatural residues to expand our investigations. The results reveal that the affinity of CF1 can be improved (2–2.5-fold) by substituting its P5 position with the small hydrophobic residues (Ile or Val) or a basic Lys. 相似文献
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Jian Jin ángel Morales-Ramos Patrick Eidam John Mecom Yue Li Carl Brooks Mark Hilfiker David Zhang Ning Wang Dongchuan Shi Pei-San Tseng Karen Wheless Brian Budzik Karen Evans Jon-Paul Jaworski Jack Jugus Lisa Leon Charlene Wu Mark Pullen Bhumika Karamshi Parvathi Rao Emma Ward Nicholas Laping Christopher Evans Colin Leach Dennis Holt Xin Su Dwight Morrow Harvey Fries Kevin Thorneloe Richard Edwards 《ACS medicinal chemistry letters》2010,1(7):316-320
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Hong Lin Mark J. Schulz Ren Xie Jin Zeng Juan I. Luengo MichaelD. Squire Rosanna Tedesco Junya Qu Karl Erhard James F. Mack Kaushik Raha Ramona Plant Cynthia M. Rominger JenniferL. Ariazi Christian S. Sherk Michael D. Schaber Jeanelle McSurdy-Freed Michael D. Spengler Charles B. Davis Mary Ann Hardwicke RalphA. Rivero 《ACS medicinal chemistry letters》2012,3(7):524-529
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Qingjie Liu Douglas G. Batt Carolyn A. Weigelt Shiuhang Yip Dauh-Rurng Wu Max Ruzanov John S. Sack Jinhong Wang Melissa Yarde Sha Li David J. Shuster Jenny H. Xie Tara Sherry Mary T. Obermeier Aberra Fura Kevin Stefanski Georgia Cornelius Purnima Khandelwal Joseph A. Tino John E. Macor Luisa Salter-Cid Rex Denton Qihong Zhao T. G. Murali Dhar 《ACS medicinal chemistry letters》2020,11(12):2510
Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure–activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis. 相似文献
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Huiqiang Zhou Dana P. Danger Steven T. Dock Lora Hawley Shane G. Roller Chari D. Smith Anthony L. Handlon 《ACS medicinal chemistry letters》2010,1(1):19-23
d-glucopyranoside inhibitors of human SGLT2 are described. The synthesis of the C-linked heterocyclic glucosides took advantage of a palladium-catalyzed cross-coupling reaction between a glucal boronate and the corresponding bromo heterocycle. The compounds have been evaluated for their human SGLT2 inhibition potential using cell-based functional transporter assays, and their structure−activity relationships have been described. Benzisothiazole-C-glucoside 16d was found to be an inhibitor of SGLT2 with an IC50 of 10 nM. 相似文献
15.
KevinM. Gayler Ke Kong Keighley Reisenauer Joseph H. Taube John L. Wood 《ACS medicinal chemistry letters》2020,11(12):2441
Staurosporine is among the most potent naturally occurring kinase inhibitors isolated to date and has served as a lead compound for numerous drug development efforts in several therapeutic areas. Herein we report that C–H borylation chemistry provides access to analogs of staurosporine that were previously inaccessible to medicinal chemists who, in the past four decades, have prepared over 1000 semisynthetic staurosporine analogs. 相似文献
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DilipK. Tosh Christopher M. Brackett Young-Hwan Jung Zhan-Guo Gao Monimoy Banerjee Brian S. J. Blagg Kenneth A. Jacobson 《ACS medicinal chemistry letters》2021,12(3):373
The heat shock protein 90 kDa (Hsp90) family of chaperones is highly sought-after for the treatment of cancer and neurodegenerative diseases. Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum localized isoform that is responsible for the maturation of proteins involved in cell adhesion and the immune response, including Toll-like receptors, immunoglobulins, and integrins. Consequently, Grp94 has been implicated in many different diseases including cancer metastasis, glaucoma, and viral infection. 5′-(N-Ethylcarboxamido)adenosine (NECA) was identified from a high-throughput screen as one of the first molecules to exhibit isoform selectivity toward Grp94, with the ethyl group projecting into a unique pocket within the ATP binding site of Grp94. This pocket has since been exploited by several groups to develop Grp94 selective inhibitors. Despite success in the development of other classes of inhibitors, relatively little work has been done to further develop inhibitors with the NECA scaffold. Unfortunately, NECA is also a potent adenosine receptor agonist, which is likely to confound any biological activity. Therefore, structure–activity relationship studies were performed on the NECA scaffold leading to the discovery of several molecules that displayed similar selectivity and affinity as the parent compound. 相似文献
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Harry R. Chobanian Yan Guo Ping Liu Marc Chioda ThomasJ. Lanza Jr. Linda Chang Theresa M. Kelly Yanqing Kan Oksana Palyha Xiao-Ming Guan DonaldJ. Marsh Joseph M. Metzger Judith N. Gorski Kate Raustad Sheng-Ping Wang AlisonM. Strack Randy Miller Jianmei Pang Maria Madeira Kathy Lyons Jasminka Dragovic MarcL. Reitman Ravi P. Nargund Linus S. Lin 《ACS medicinal chemistry letters》2012,3(3):252-256
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Zirui Lü Xiaona Li Kebin Li Cong Wang Tingting Du Wei Huang Ming Ji Changhong Li Fengrong Xu Ping Xu Yan Niu 《ACS medicinal chemistry letters》2021,12(5):696
We identified nitazoxanide (NTZ) as a moderate STAT3 pathway inhibitor through immunoblot analysis and a cell-based IL-6/JAK/STAT3 pathway activation assay. A series of thiazolide derivatives were designed and synthesized to further validate the thiazolide scaffold as STAT3 inhibitors. Eight out of 25 derivatives displayed potencies greater than that of NTZ, and their STAT3 pathway inhibitory activities were found to be significantly correlated with their antiproliferative activities in HeLa cells. Derivatives 15 and 24 were observed to be more potent than the positive control WP1066, which is under phase I clinical trials. Compared with NTZ, 15 also exhibited much improved in vivo pharmacokinetic parameters in rats and efficacies against proliferations in multiple cancer cell lines, indicating a broad-spectrum effect of these thiazolides as antitumor agents targeted on STAT3. 相似文献
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Jeffrey W. Jacobs Michael R. Leadbetter Noah Bell Samantha Koo-McCoy Christopher W. Carreras Limin He Jill Kohler Kenji Kozuka Eric D. Labont Marc Navre Andrew G. Spencer Dominique Charmot 《ACS medicinal chemistry letters》2022,13(7):1043
We present herein the design, synthesis, and optimization of gut-restricted inhibitors of Na+/H+ exchanger isoform 3 (NHE3). NHE3 is predominantly expressed in the kidney and gastrointestinal tract where it acts as the major absorptive sodium transporter. We desired minimally systemic agents that would block sodium absorption in the gastrointestinal tract but avoid exposure in the kidney. Starting with a relatively low-potency highly bioavailable hit compound (1), potent and minimally absorbed NHE3 inhibitors were designed, culminating with the discovery of tenapanor (28). Tenapanor has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of irritable bowel syndrome with constipation in adults. 相似文献