共查询到20条相似文献,搜索用时 15 毫秒
1.
Hirsch BM Hao Y Li X Wesdemiotis C Wang Z Zheng W 《Bioorganic & medicinal chemistry letters》2011,21(16):4753-4757
In the current study, we have identified Nε-thiocarbamoyl-lysine (TuAcK) as a general sirtuin inhibitory warhead which was shown to be able to confer potent sirtuin inhibition. This inhibition was also shown to be mechanism-based in that the TuAck residue was able to be processed by a sirtuin enzyme with the formation of a stalled S-alkylamidate intermediate. 相似文献
2.
David Marcoux Lan-Ying Qin Zheming Ruan Qing Shi Qian Ruan Carolyn Weigelt Hongchen Qiu Gary Schieven John Hynes Rajeev Bhide Michael Poss Joseph Tino 《Bioorganic & medicinal chemistry letters》2017,27(13):2849-2853
Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined. 相似文献
3.
Mathieu Bibian Ronald J. Rahaim Jun Yong Choi Yoshihiko Noguchi Stephan Schürer Weimin Chen Shima Nakanishi Konstantin Licht Laura H. Rosenberg Lin Li Yangbo Feng Michael D. Cameron Derek R. Duckett John L. Cleveland William R. Roush 《Bioorganic & medicinal chemistry letters》2013,23(15):4374-4380
The development of a series of potent and highly selective casein kinase 1δ/ε (CK1δ/ε) inhibitors is described. Starting from a purine scaffold inhibitor (SR-653234) identified by high throughput screening, we developed a series of potent and highly kinase selective inhibitors, including SR-2890 and SR-3029, which have IC50 ? 50 nM versus CK1δ. The two lead compounds have ?100 nM EC50 values in MTT assays against the human A375 melanoma cell line and have physical, in vitro and in vivo PK properties suitable for use in proof of principle animal xenograft studies against human cancer cell lines. 相似文献
4.
Toshihiro Hamajima Fumie Takahashi Koji Kato Yukihito Sugano Susumu Yamaki Ayako Moritomo Satoshi Kubo Koji Nakamura Kaoru Yamagami Nozomu Hamakawa Koji Yokoo Hidehiko Fukahori 《Bioorganic & medicinal chemistry》2018,26(14):3917-3924
Chemical optimization of pyrazolopyridine 1, focused on cellular potency, isoform selectivity and microsomal stability, led to the discovery of the potent, selective and orally available PI3Kδ inhibitor 5d. On the basis of its desirable potency, selectivity and pharmacokinetic profiles, 5d was tested in the trinitrophenylated aminoethylcarboxymethyl-Ficoll (TNP-Ficoll)-induced antibody production model, and showed higher antibody inhibition than a 4-fold oral dose of the starting compound 1. These excellent results suggest that 5d is a potential candidate for further studies in the treatment of autoimmune diseases and leukocyte malignancies. 相似文献
5.
Shantanu Pal Won Jun Choi Seung Ah Choe Cara L. Heller Zhan-Guo Gao Moshe Chinn Kenneth A. Jacobson Xiyan Hou Sang Kook Lee Hea Ok Kim Lak Shin Jeong 《Bioorganic & medicinal chemistry》2009,17(10):3733-3738
On the basis of potent and selective binding affinity of truncated 4′-thioadenosine derivatives at the human A3 adenosine receptor (AR), their bioisosteric 4′-oxo derivatives were designed and synthesized from commercially available 2,3-O-isopropylidene-d-erythrono lactone. The derivatives tested in AR binding assays were substituted at the C2 and N6 positions. All synthesized nucleosides exhibited potent and selective binding affinity at the human A3 AR. They were less potent than the corresponding 4′-thio analogues, but showed still selective to other subtypes. The 2-Cl series generally were better than the 2-H series in view of binding affinity and selectivity. Among compounds tested, compound 5d (X = Cl, R = 3-bromobenzyl) showed the highest binding affinity (Ki = 13.0 ± 6.9 nM) at the hA3 AR with high selectivity (at least 88-fold) in comparison to other AR subtypes. Like the corresponding truncated 4′-thio series, compound 5d antagonized the action of an agonist to inhibit forskolin-stimulated adenylate cyclase in hA3 AR-expressing CHO cells. Although the 4′-oxo series were less potent than the 4′-thio series, this class of human A3 AR antagonists is also regarded as another good template for the design of A3 AR antagonists and for further drug development. 相似文献
6.
Elena Lenci Riccardo Innocenti Tommaso Di Francescantonio Gloria Menchi Francesca Bianchini Alessandro Contini Andrea Trabocchi 《Bioorganic & medicinal chemistry》2019,27(9):1891-1902
MMP2 and MMP9, also called gelatinases, play a primary role in the angiogenic switch, as a fundamental step of tumor progression, and show high degree of structural similarity. Clinically successful gelatinase inhibitors need to be highly selective as opposite effects have been found for the two enzymes, and the S1′ subsite is the major driver to attain selective and potent inhibitors. The synthesis of d-proline-derived hydroxamic acids containing diverse appendages at the amino group, varying in length and decoration allowed to give insight on the MMP2/MMP9 selectivity around the S1′ subsite, resulting in the identification of sub-nanomolar compounds with high selectivity up to 730. Molecular docking studies revealed the existence of an additional hydrophobic channel at the bottom of S1′ subsite for MMP2 enzyme useful to drive selectivity towards such gelatinase. 相似文献
7.
Albert Enz Dominik Feuerbach Mathias U. Frederiksen Conrad Gentsch Konstanze Hurth Werner Müller Joachim Nozulak Bernard L. Roy 《Bioorganic & medicinal chemistry letters》2009,19(5):1287-1291
A novel class of α7 nicotinic acetylcholine receptor (nAChR) agonists has been discovered through high-throughput screening. The cis γ-lactam scaffold has been optimized to reveal highly potent and selective α7 nAChR agonists with in vitro activity and selectivity and with good brain penetration in mice. 相似文献
8.
Michael S. Malamas Keith Barnes Matthew Johnson Yu Hui Ping Zhou Jim Turner Yun Hu Erik Wagner Kristi Fan Rajiv Chopra Andrea Olland Jonathan Bard Menelas Pangalos Peter Reinhart Albert J. Robichaud 《Bioorganic & medicinal chemistry》2010,18(2):630-639
The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as β-secretase inhibitors is reported. The more potent and selective analogs demonstrate low nanomolar potency for the BACE1 enzyme as measured in a FRET assay, and exhibit comparable activity in a cell-based (ELISA) assay. In addition, these pyridine-aminohydantoins are highly selectivity (>500×) against the other structurally related aspartyl proteases BACE2, cathepsin D, pepsin and renin.Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported aminohydantoin 3a. We have taken advantage of the amino acid difference between the BACE1 and BACE2 at the S2′ pocket (BACE1 Pro70 changed to BACE2 Lys86) to build ligands with >500-fold selectivity against BACE2. The addition of large substituents on the targeted ligand at the vicinity of this aberration has generated a steric conflict between the ligand and these two proteins, thus impacting the ligand’s affinity and selectivity. These ligands have also shown an exceptional selectivity against cathepsin D (>5000-fold) as well as the other aspartyl proteases mentioned. One of the more potent compounds (S)-39 displayed an IC50 value for BACE1 of 10 nM, and exhibited cellular activity with an EC50 value of 130 nM in the ELISA assay. 相似文献
9.
Ina Terstiege Matthew Perry Jens Petersen Christian Tyrchan Tor Svensson Helena Lindmark Linda Öster 《Bioorganic & medicinal chemistry letters》2017,27(3):679-687
A novel class of potent PI3Kδ inhibitors with >1000-fold selectivity against other class I PI3K isoforms is described. Optimization of the substituents on a triazole aminopyrazine scaffold, emerging from an in-house PI3Kα program, turned moderately selective PI3Kδ compounds into highly potent and selective PI3Kδ inhibitors. These efforts resulted in a series of aminopyrazines with PI3Kδ IC50 ? 1 nM in the enzyme assay, some of the most selective PI3Kδ inhibitors published to date, with a cell potency in a JeKo-cell assay of 20–120 nM. 相似文献
10.
《Bioorganic & medicinal chemistry》2016,24(18):4206-4217
A novel thienopyrimidinone analog was discovered as a potent and highly selective TAK1 inhibitor using the SBDD approach. TAK1 plays a key role in inflammatory and immune signaling, so TAK1 is considered to be an attractive molecular target for the treatment of human diseases (inflammatory disease, cancer, etc.). After the hit compound had been obtained, our modifications successfully increased TAK1 inhibitory activity and solubility, but metabolic stability was still unsatisfactory. To improve metabolic stability, we conducted metabolic identification. Although the obtained metabolite was fortunately a potent TAK1 inhibitor, its kinase selectivity was low. Subsequently, to achieve high kinase selectivity, we used SBDD to follow two strategies: one targeting unique amino acid residues in TAK1, especially the combination of Ser111 and Asn114; the other decreasing the interaction with Tyr106 at the hinge position in TAK1. As expected, our designed compound showed an excellent kinase selectivity profile in both an in-house and a commercially available panel assay of over 420 kinases and also retained its potent TAK1 inhibitory activity (TAK1 IC50 = 11 nM). 相似文献
11.
John I. Trujillo James R. Kiefer Wei Huang Atli Thorarensen Li Xing Nicole L. Caspers Jacqueline E. Day Karl J. Mathis Kuniko K. Kretzmer Beverley A. Reitz Robin A. Weinberg Roderick A. Stegeman Ann Wrightstone Lori Christine Robert Compton Xiong Li 《Bioorganic & medicinal chemistry letters》2009,19(3):908-911
The inhibition of PKC-ζ has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-ζ). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH2 derivative. The analog displays good selectivity over other PKC isoforms (α, βII, γ, δ, ε, μ, θ, η and ι/λ) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled). 相似文献
12.
Sonja Nordhoff Silvia Cerezo-Gálvez Holger Deppe Oliver Hill Meritxell López-Canet Christian Rummey Meinolf Thiemann Victor G. Matassa Paul J. Edwards Achim Feurer 《Bioorganic & medicinal chemistry letters》2009,19(15):4201-4203
Modifications of DPP-4 inhibitor 5, that was discovered by structure based design, are described and structure–activity relationships discussed. With analogue 7k one of the most potent non-covalent inhibitors of DPP-4 reported to date (IC50 = 0.38 nM) was discovered. X-ray structure of inhibitor 7k bound to DPP-4 revealed a hydrogen bonding interaction with Q553. First successful efforts in balancing overall properties, as demonstrated by improved metabolic stability, highlight the potential of this series. 相似文献
13.
Won Jun Choi Hyuk Woo Lee Hea Ok Kim Moshe Chinn Zhan-Guo Gao Amit Patel Kenneth A. Jacobson Hyung Ryong Moon Young Hoon Jung Lak Shin Jeong 《Bioorganic & medicinal chemistry》2009,17(23):8003-8011
On the basis of a bioisosteric rationale, 4′-thionucleoside analogues of IB-MECA (N6-(3-Iodo-benzyl)-9-(5′-methylaminocarbonyl-β-d-ribofuranosyl)adenine), which is a potent and selective A3 adenosine receptor (AR) agonist, were synthesized from d-gulonic acid γ-lactone. The 4′-thio analogue (5h) of IB-MECA showed extremely high binding affinity (Ki = 0.25 nM) at the human A3AR and was more potent than IB-MECA (Ki = 1.4 nM). Bulky substituents at the 5′-uronamide position, such as cyclohexyl and 2-methylbenzyl, in this series of 2-H nucleoside derivatives were tolerated in A3AR binding, although small alkyl analogues were more potent. 相似文献
14.
15.
Selective cytochrome P450 (CYP) 1B1 inhibition has potential as an anticancer strategy that is unrepresented in the current clinical arena. For development of a selective inhibitor, we focused on the complexity caused by sp3-hybridized carbons and synthesized a series of benzo[h]chromone derivatives linked to a non-aromatic B-ring using α-naphthoflavone (ANF) as the lead compound. Ring structure comparison suggested compound 37 as a suitable cyclohexyl-core with improved solubility. Structural evolution of 37 produced the azide-containing cis-49a, which had good properties in three important respects: (1) selectivity for CYP1B1 over CYP1A1 and CYP1A2 (120-times and 150-times, respectively), (2) greater inhibitory potency of >2 times that of ANF, and (3) improved solubility. The corresponding aromatic B-ring compound 59a showed low selectivity and poor solubility. To elucidate the binding mode, we performed X-ray crystal structure analysis, which revealed the interaction mode and explained the subtype selectivity of cis-49a. 相似文献
16.
Michael S. Malamas Keith Barnes Yu Hui Matthew Johnson Frank Lovering Jeff Condon William Fobare William Solvibile Jim Turner Yun Hu Eric S. Manas Kristi Fan Andrea Olland Rajiv Chopra Jonathan Bard Menelas N. Pangalos Peter Reinhart Albert J. Robichaud 《Bioorganic & medicinal chemistry letters》2010,20(7):2068-2073
The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid in Alzheimer’s disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the topological polar surface area or TPSA), which is unfavorable for crossing the blood–brain barrier. Herein, we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acylguanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration. X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network. 相似文献
17.
Xiaocong M. Ye Andrei W. Konradi Minghua Sun Shendong Yuan Danielle L. Aubele Michael Dappen Darren Dressen Albert W. Garofalo Jacek J. Jagodzinski Lee Latimer Gary D. Probst Hing L. Sham David Wone Ying-zi Xu Daniel Ness Elizabeth Brigham Grace T. Kwong Chris Willtis Guriqbal S. Basi 《Bioorganic & medicinal chemistry letters》2013,23(4):996-1000
Structure–activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted. 相似文献
18.
Brian S. Safina Zachary K. Sweeney Jun Li Bryan K. Chan Angelina Bisconte Diane Carrera Georgette Castanedo Michael Flagella Robert Heald Cristina Lewis Jeremy M. Murray Jim Nonomiya Jodie Pang Steve Price Karin Reif Laurent Salphati Eileen M. Seward Binqing Wei Daniel P. Sutherlin 《Bioorganic & medicinal chemistry letters》2013,23(17):4953-4959
In an effort to identify potent and isoform selective inhibitors of PI3Kδ, GNE-293 (34) was identified. Inhibitor 2 was found to induce micronuclei formation in both the MNT and HCA in vitro assays. Compounds testing negative for genotoxicity were successfully identified through modifications of the 2-benzimidazole substituent and the methylene moiety to disrupt planarity. A variety of heteroatom linkers were explored to examine their effect on potency and isoform selectivity by restricting torsional angles to favor ligand interactions with PI3Kδ’s Trp760. These modifications also resulted in an improved in vivo pharmacokinetic profile. 相似文献
19.
Dominique Lesuisse Gilles Tiraboschi Alain Krick Pierre-Yves Abecassis Gilles Dutruc-Rosset Didier Babin Frank Halley Fabienne Châtreau Sylvette Lachaud Alain Chevalier Dominique Quarteronet Marie-Claude Burgevin Céline Amara Philippe Bertrand Thomas Rooney 《Bioorganic & medicinal chemistry letters》2010,20(7):2344-2349
From potent and selective inhibitors of GSK3β displaying CYP1A2 inhibition and poor PK properties, mostly linked to metabolic instability and in vivo hydrolysis of the amide bond, we were able to obtain safe and orally available inhibitors with good half lives. 相似文献
20.
《Bioorganic & medicinal chemistry letters》2020,30(1):126715
A high-throughput screening (HTS) campaign identified a class of heteroaryl piperazines with excellent baseline affinity and selectivity for phosphoinositide 3-kinase δ (PI3Kδ) over closely related isoforms. Rapid evaluation and optimization of structure-activity relationships (SAR) for this class, leveraging the modular nature of this scaffold, facilitated development of this hit class into a series of potent and selective inhibitors of PI3Kδ. This effort culminated in the identification of 29, which displayed excellent potency in enzyme and cell-based assays, as well as favorable pharmacokinetic and off-target profiles. 相似文献