共查询到20条相似文献,搜索用时 46 毫秒
1.
Yu Jia Tan Ming Li Gregory Adrian Gunawan Samuel Agyei Nyantakyi Thomas Dick Mei-Lin Go Yulin Lam 《ACS medicinal chemistry letters》2021,12(5):704
Indolecarboxamides are potent but poorly soluble mycobactericidal agents. Here we found that modifying the incipient scaffold by amide–amine substitution and replacing the indole ring with benzothiophene or benzoselenophene led to striking (10–20-fold) improvements in solubility. Potent activity could be achieved without the carboxamide linker but not in the absence of the indole ring. The indolylmethylamine, N-cyclooctyl-6-trifluoromethylindol-2-ylmethylamine (33, MIC90Mtb 0.13 μM, MBC99.9Mtb 0.63 μM), exemplifies a promising member that is more soluble and equipotent to its carboxamide equivalent. It is also an inhibitor of the mycolate transporter MmpL3, a property shared by the methylamines of benzothiophene and benzoselenophene. 相似文献
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MalcolmP. Huestis Matthew R. Durk Charles Eigenbrot Paul Gibbons Thomas L. Hunsaker Hank La Dennis H. Leung Wendy Liu Shiva Malek Mark Merchant John G. Moffat Christine S. Muli Christine J. Orr Brendan T. Parr Frances Shanahan Christopher J. Sneeringer Weiru Wang Ivana Yen Jianping Yin Joachim Rudolph Michael Siu 《ACS medicinal chemistry letters》2021,12(5):791
Structure-based optimization of a set of aryl urea RAF inhibitors has led to the identification of Type II pan-RAF inhibitor GNE-9815 (7), which features a unique pyrido[2,3-d]pyridazin-8(7H)-one hinge-binding motif. With minimal polar hinge contacts, the pyridopyridazinone hinge binder moiety affords exquisite kinase selectivity in a lipophilic efficient manner. The improved physicochemical properties of GNE-9815 provided a path for oral dosing without enabling formulations. In vivo evaluation of GNE-9815 in combination with the MEK inhibitor cobimetinib demonstrated synergistic MAPK pathway modulation in an HCT116 xenograft mouse model. To the best of our knowledge, GNE-9815 is among the most highly kinase-selective RAF inhibitors reported to date. 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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Emily C. Cherney Liping Zhang Susheel Nara Xiao Zhu Johnni Gullo-Brown Derrick Maley Tai-An Lin John T. Hunt Christine Huang Zheng Yang Celia Darienzo Lorell Discenza Asoka Ranasinghe Mary Grubb Theresa Ziemba Sarah C. Traeger Xin Li Kathy Johnston Lisa Kopcho Mark Fereshteh Kimberly Foster Kevin Stefanski Joseph Fargnoli Jesse Swanson Jennifer Brown Diane Delpy Steven P. Seitz Robert Borzilleri Gregory Vite Aaron Balog 《ACS medicinal chemistry letters》2021,12(2):288
Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase enzyme implicated in cancer immune response. This account details the discovery of BMS-986242, a novel IDO1 inhibitor designed for the treatment of a variety of cancers including metastatic melanoma and renal cell carcinoma. Given the substantial interest around this target for cancer immunotherapy, we sought to identify a structurally differentiated clinical candidate that performs comparably to linrodostat (BMS-986205) in terms of both in vitro potency and in vivo pharmacodynamic effect in a mouse xenograft model. On the basis of its preclinical profile, BMS-986242 was selected as a candidate for clinical development. 相似文献
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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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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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Donghui Qin Xiaojuan Lin Zhi Liu Yan Chen Zhiliu Zhang Chengde Wu Linlin Liu Yan Pan Sylvie Laquerre John Emery Jeff Fergusson Kimberly Roland Rick Keenan Allen Oliff Sanjay Kumar Mui Cheung Dai-Shi Su 《ACS medicinal chemistry letters》2021,12(6):1005
We report herein the discovery of quinazolindiones as potent and selective tankyrase inhibitors. Elucidation of the structure–activity relationship of the lead compound 1g led to truncated analogues that have good potency in cells, pharmacokinetic (PK) properties, and excellent selectivity. Compound 21 exhibited excellent potencies in cells and proliferation studies, good selectivity, in vitro activities, and an excellent PK profile. Compound 21 also inhibited H292 xenograft tumor growth in nude mice. The synthesis, biological, pharmacokinetic, in vivo efficacy studies, and safety profiles of compounds are presented. 相似文献
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Christian Harcken Johanna Csengery Michael Turner Lifen Wu Shuang Liang Robert Sibley Steven Brunette Mark Labadia Kathleen Hoyt Anita Wayne Thomas Wieckowski Gregg Davis Mark Panzenbeck Donald Souza Stanley Kugler Donna Terenzio Delphine Collin Dustin Smith Ryan M. Fryer Yin-Chao Tseng Jrg P. Hehn Kim Fletcher Robert O. Hughes 《ACS medicinal chemistry letters》2021,12(1):143
11.
《ACS medicinal chemistry letters》2021,12(5):827
Structure–activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORγt inverse agonist series represented by 1 with heterocyclic moieties led to the identification of three novel aza analogs 5–7. The hexahydropyrrolo[3,2-f]quinoline series 5 (X = N, Y = Z=CH) showed potency and metabolic stability comparable to series 1 but with improved in vitro membrane permeability and serum free fraction. This structural modification was applied to the hexahydrocyclopentanaphthalene series 3, culminating in the discovery of 8e as a potent and selective RORγt inverse agonist with an excellent in vitro profile, good pharmacokinetic properties, and biologic-like in vivo efficacy in preclinical models of rheumatoid arthritis and psoriasis. 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
13.
Brandon A. Vara Samuel M. Levi Abdelghani Achab David A. Candito Xavier Fradera Charles A. Lesburg Shuhei Kawamura Brian M. Lacey Jongwon Lim Joey L. Methot Zangwei Xu Haiyan Xu Dustin M. Smith Jennifer A. Piesvaux J. Richard Miller Mark Bittinger Sheila H. Ranganath David J. Bennett Erin F. DiMauro Alexander Pasternak 《ACS medicinal chemistry letters》2021,12(4):653
Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo, supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure–activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising in vitro profiles. 相似文献
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Sicheng Zhang Luis O. Romero Shanshan Deng Jiaxing Wang Yong Li Lei Yang David J. Hamilton Duane D. Miller Francesca-Fang Liao Julio F. Cordero-Morales Zhongzhi Wu Wei Li 《ACS medicinal chemistry letters》2021,12(4):572
The overactivation of transient receptor potential canonical 3 (TRPC3) is associated with neurodegenerative diseases and hypertension. Pyrazole 3 (Pyr3) is reported as the most selective TRPC3 inhibitor, but it has two inherent structural limitations: (1) the labile ester moiety leads to its rapid hydrolysis to the inactive Pyr8 in vivo, and (2) the alkylating trichloroacrylic amide moiety is known to be toxic. To circumvent these limitations, we designed a series of conformationally restricted Pyr3 analogues and reported that compound 20 maintains high potency and selectivity for human TRPC3 over its closely related TRP channels. It has significantly improved metabolic stability compared with Pyr3 and has a good safety profile. Preliminary evaluation of 20 demonstrated its ability to rescue Aβ-induced neuron damage with similar potency to that of Pyr3 in vitro. Collectively, these results suggest that 20 represents a promising scaffold to potentially ameliorate the symptoms associated with TRPC3-mediated neurological and cardiovascular disorders. 相似文献
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RomanM. Mrozowski Rajender Vemula Bulan Wu Qi Zhang Benjamin R. Schroeder Michael K. Hilinski David E. Clark Sidney M. Hecht George A. O’Doherty Deborah A. Lannigan 《ACS medicinal chemistry letters》2013,4(2):175-179
l-rhamnopyranoside)) has been shown to be an RSK selective inhibitor.
However, the Ki for SL0101 is 1 μM
with a half-life of less than 30 min in vivo. To
identify analogues with improved efficacy we designed a set of analogues
based on the crystallographic model of SL0101 in complex with the
RSK2 N-terminal kinase domain. We identified an analogue with a 5″-n-propyl group on the rhamnose that has >40-fold improved
affinity for RSK relative to SL0101 in an in vitro kinase assay. This analogue preferentially inhibited the proliferation
of the human breast cancer line, MCF-7, versus the normal untransformed
breast line, MCF-10A, which is consistent with results using SL0101.
However, the efficacy of the 5″-n-propyl analogue
to inhibit MCF-7 proliferation was only 2-fold better than for SL0101,
which we hypothesize is due to limited membrane permeability. The
improved affinity of the 5″-n-propyl analogue
for RSK will aid in the design of future compounds for in
vivo use. 相似文献
18.
Yanran Lu Jonathan L. Papa Sheri Nolan Anthony English Justin T. Seffernick Nicholas Shkolnikov Josh Powell Steffen Lindert Daniel J. Wozniak Jack Yalowich Mark J. Mitton-Fry 《ACS medicinal chemistry letters》2020,11(12):2446
In recent years, novel bacterial topoisomerase inhibitors (NBTIs) have been developed as future antibacterials for treating multidrug-resistant bacterial infections. A series of dioxane-linked NBTIs with an amide moiety has been synthesized and evaluated. Compound 3 inhibits DNA gyrase, induces the formation of single strand breaks to bacterial DNA, and achieves potent antibacterial activity against a variety of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Optimization of this series of analogues led to the discovery of a subseries of compounds (22–25) with more potent anti-MRSA activity, dual inhibition of DNA gyrase and topoisomerase IV, and the ability to induce double strand breaks through inhibition of S. aureus DNA gyrase. 相似文献
19.
William T. McElroy Zheng Tan Ginny Ho Sunil Paliwal Guoqing Li W. Michael Seganish Deen Tulshian James Tata ThierryO. Fischmann Christopher Sondey Hong Bian Loretta Bober James Jackson CharlesG. Garlisi Kristine Devito James Fossetta Daniel Lundell Xiaoda Niu 《ACS medicinal chemistry letters》2015,6(6):677-682
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NathalieM. Grob Roger Schibli Martin Bh Ibai E. Valverde Thomas L. Mindt 《ACS medicinal chemistry letters》2021,12(4):585
1,5-Disubstituted 1,2,3-triazoles (1,5-Tz) are considered bioisosteres of cis-amide bonds. However, their use for enhancing the pharmacological properties of peptides or proteins is not yet well established. Aiming to illustrate their utility, we chose the peptide conjugate [Nle15]MG11 (DOTA-dGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) as a model compound since it is known that the cholecystokinin-2 receptor (CCK2R) is able to accommodate turn conformations. Analogs of [Nle15]MG11 incorporating 1,5-Tz in the backbone were synthesized and radiolabeled with lutetium-177, and their pharmacological properties (cell internalization, receptor binding affinity and specificity, plasma stability, and biodistribution) were evaluated and compared with [Nle15]MG11 as well as their previously reported analogs bearing 1,4-disubstituted 1,2,3-triazoles. Our investigations led to the discovery of novel triazole-modified analogs of [Nle15]MG11 with nanomolar CCK2R-binding affinity and 2-fold increased tumor uptake. This study illustrates that substitution of amides by 1,5-disubstituted 1,2,3-triazoles is an effective strategy to enhance the pharmacological properties of biologically active peptides. 相似文献