共查询到20条相似文献,搜索用时 15 毫秒
1.
Todd A. Brugel Reed W. Smith Michael Balestra Christopher Becker Thalia Daniels Gerard M. Koether Scott R. Throner Laura M. Panko Dean G. Brown Ruifeng Liu John Gordon Matthew F. Peters 《Bioorganic & medicinal chemistry letters》2010,20(18):5405-5410
Further structure activity relationship studies on a previously reported 8-azabicyclo[3.2.1]octan-3-yloxy-benzamide series of potent and selective kappa opioid receptor antagonists is discussed. Modification of the pendant N-substitution to include a cyclohexylurea moiety produced analogs with greater in vitro opioid and hERG selectivity such as 12 (κ IC50 = 172 nM, μ:κ ratio = 93, δ:κ ratio = >174, hERG IC50 = >33 μM). Changes to the linker conformation and identity as well as to the benzamide ring moiety were also investigated. 相似文献
2.
Roland E. Dolle Mathieu Michaut Blanca Martinez-Teipel Pamela R. Seida Christopher W. Ajello Alison L. Muller Robert N. DeHaven Patrick J. Carroll 《Bioorganic & medicinal chemistry letters》2009,19(13):3647-3650
Cyclic tetrapeptide c[Phe-pro-Phe-trp] 2, a diastereomer of CJ-15,208 (1), was identified as a potent dual κ/μ opioid receptor antagonist devoid of δ opioid receptor affinity against cloned human receptors: Ki (2) = 3.8 nM (κ), 30 nM (μ); IC50 ([35S]GTPγS binding) = 140 nM (κ), 21 nM (μ). The d-tryptophan residue rendered 2 ca. eightfold and fourfold more potent at κ and μ, respectively, than the corresponding l-configured tryptophan in the natural product 1. Phe analogs 3–10, designed to probe the effect of substituents on receptor affinity and selectivity, possessed Ki values ranging from 14 to 220 nM against the κ opioid receptor with μ/κ ratios of 0.45–3.0. An alanine scan of 2 yielded c[Ala-pro-Phe-trp] 12, an analog equipotent to 2. Agents 2 and 12 were pure antagonists in vitro devoid of agonist activity. Ac-pro-Phe-trp-Phe-NH2 16 and Ac-Phe-trp-Phe-pro-NH2 17 two of the eight possible acyclic peptides derived from 1 and 2, were selective, modestly potent μ ligands: Ki (16) = 340 nM (μ); Ki (17) = 360 nM (μ). 相似文献
3.
Wen-Ting Xu Ning Jin Jing Xu Yun-Gen Xu Qiu-Juan Wang Qi-Dong You 《Bioorganic & medicinal chemistry letters》2009,19(12):3283-3287
A novel series of substituted benzoylguanidine derivatives were designed and synthesized as potent NHE1 inhibitors. Most compounds can significantly inhibit NHE1-mediated platelet swelling in a concentration-dependent manner, among which compound 5f (IC50 = 3.60 nM) and 5l (IC50 = 4.48 nM) are 18 and 14 times respectively more potent than cariporide (IC50 = 65.0 nM). Furthermore, when tested in vivo and in vitro, compound 5f showed superior cardioprotective effects against SD rat myocardial ischemic-reperfusion injury over cariporide, representing a promising lead compound for further exploration. 相似文献
4.
《Bioorganic & medicinal chemistry letters》2014,24(1):337-343
A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50 = 2.5 nM, A2780 cell proliferation IC50 = 9.7 nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2014,24(22):5175-5180
5-(3,4,5-Trimethoxybenzoyl)-4-amimopyrimidine derivatives were found as a novel chemical class of potent and highly selective phosphodiesterase 5 inhibitors. A pseudo-ring formed by an intramolecular hydrogen bond constrained the conformation of 3-chloro-4-methoxybenzylamino and 3,4,5-trimethoxybenzoyl substituents and led to the discovery of T-6932 (19a) with a potent PDE5 inhibitory activity (IC50 = 0.13 nM) and a high selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2400). Further modification at the 2-position of T-6932 resulted in the finding of 26, which exhibited potent relaxant effects on isolated rabbit corpus cavernosum (EC30 = 11 nM) with a high PDE5 selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2800). 相似文献
6.
Taiji Goto Akiko Shiina Toshiharu Yoshino Kiyoshi Mizukami Kazuki Hirahara Osamu Suzuki Yoshitaka Sogawa Tomoko Takahashi Tsuyoshi Mikkaichi Naoki Nakao Mizuki Takahashi Masashi Hasegawa Shigeki Sasaki 《Bioorganic & medicinal chemistry letters》2013,23(11):3325-3328
2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50 = 150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50 = 25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50 = 7.5 nM) and TNF-α production in mouse splenocytes (IC50 = 9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50 = 18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand–enzyme complex. 相似文献
7.
《Bioorganic & medicinal chemistry letters》2014,24(4):1228-1231
Tertiary hydroxyl class of C-imidazole bridgehead azaheptapyridine FPT inhibitors were prepared in an attempt to block in vivo oxidation of secondary hydroxyl series. One representative compound 5a exhibited potent enzyme (IC50 = 1.4 nM) and cellular activities (soft agar IC50 = 1.3 nM) with excellent oral pharmacokinetic profiles in rats, mice, monkeys and dogs. The in vivo study in wap-ras TG mouse models showed dose dependent tumor growth inhibition and regression. 相似文献
8.
Michael K. Ameriks Scott D. Bembenek Matthew T. Burdett Ingrid C. Choong James P. Edwards Damara Gebauer Yin Gu Lars Karlsson Hans E. Purkey Bart L. Staker Siquan Sun Robin L. Thurmond Jian Zhu 《Bioorganic & medicinal chemistry letters》2010,20(14):4060-4064
A pyridazin-4-one fragment 4 (hCatS IC50 = 170 μM) discovered through Tethering was modeled into cathepsin S and predicted to overlap in S2 with the tetrahydropyridinepyrazole core of a previously disclosed series of CatS inhibitors. This fragment served as a template to design pyridazin-3-one 12 (hCatS IC50 = 430 nM), which also incorporates P3 and P5 binding elements. A crystal structure of 12 bound to Cys25Ser CatS led to the synthesis of the potent diazinone isomers 22 (hCatS IC50 = 60 nM) and 27 (hCatS IC50 = 40 nM). 相似文献
9.
Peter S. Dragovich Kenneth W. Bair Timm Baumeister Yen-Ching Ho Bianca M. Liederer Xiongcai Liu Yongbo Liu Thomas O’Brien Jason Oeh Deepak Sampath Nicholas Skelton Leslie Wang Weiru Wang Hongxing Wu Yang Xiao Po-wai Yuen Mark Zak Lei Zhang Xiaozhang Zheng 《Bioorganic & medicinal chemistry letters》2013,23(17):4875-4885
Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 = 11 nM; PC-3 antiproliferative IC50 = 36 nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 = 10 nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined. 相似文献
10.
Rie Nishikawa-Shimono Yoshinori Sekiguchi Takeshi Koami Madoka Kawamura Daisuke Wakasugi Kazuhito Watanabe Shunichi Wakahara Kayo Kimura Susumu Yamanobe Tetsuo Takayama 《Bioorganic & medicinal chemistry》2013,21(24):7674-7685
In this study, we describe the synthesis and structure–activity relationship (SAR) of a series of isoquinoline chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTH2) antagonists. TASP0376377 (15-20), one of the most potent compounds, showed a potent binding affinity (IC50 = 19 nM) in addition to the excellent functional antagonist activity (IC50 = 13 nM). Moreover, the efficacy of this compound in a chemotaxis assay (IC50 = 23 nM) was in good agreement with its potency as a CRTH2 antagonist. In addition, 15-20 exhibited greater selectivity in binding to CRTH2 than to the DP1 prostanoid receptor (IC50 >1 μM) or the enzymes COX-1 and COX-2 (IC50 >10 μM). 相似文献
11.
Robert J. Cherney John B. Brogan Ruowei Mo Yvonne C. Lo Gengjie Yang Persymphonie B. Miller Peggy A. Scherle Bruce F. Molino Percy H. Carter Carl P. Decicco 《Bioorganic & medicinal chemistry letters》2009,19(3):597-601
A series of trisubstituted cyclohexanes was designed, synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the identification of two distinct substitution patterns about the cyclohexane ring as potent and selective CCR2 antagonists. Compound 36 exhibited excellent binding (CCR2 IC50 = 2.4 nM) and functional antagonism (calcium flux IC50 = 2.0 nM and chemotaxis IC50 = 5.1 nM). 相似文献
12.
Mohamed S. Gomaa Andrew S.T. Lim S.C. Wilson Lau Ann-Marie Watts Nicola A. Illingworth Caroline E. Bridgens Gareth J. Veal Christopher P.F. Redfern Andrea Brancale Jane L. Armstrong Claire Simons 《Bioorganic & medicinal chemistry》2012,20(20):6080-6088
The role of all-trans-retinoic acid (ATRA) in the development and maintenance of many epithelial and neural tissues has raised great interest in the potential of ATRA and related compounds (retinoids) as pharmacological agents, particularly for the treatment of cancer, skin, neurodegenerative and autoimmune diseases. The use of ATRA or prodrugs as pharmacological agents is limited by a short half-life in vivo resulting from the activity of specific ATRA hydroxylases, CYP26 enzymes, induced by ATRA in liver and target tissues. For this reason retinoic acid metabolism blocking agents (RAMBAs) have been developed for treating cancer and a wide range of other diseases.The synthesis, CYP26A1 inhibitory activity and molecular modeling studies of novel methyl 3-[4-(arylamino)phenyl]-3-(azole)-2,2-dimethylpropanoates are presented. From this series of compounds clear SAR can be derived for 4-substitution of the phenyl ring with electron-donating groups more favourable for inhibitory activity. Both the methylenedioxyphenyl imidazole (17, IC50 = 8 nM) and triazole (18, IC50 = 6.7 nM) derivatives were potent inhibitors with additional binding interactions between the methylenedioxy moiety and the CYP26 active site likely to be the main factor. The 6-bromo-3-pyridine imidazole 15 (IC50 = 5.7 nM) was the most active from this series compared with the standards liarozole (IC50 = 540 nM) and R116010 (IC50 = 10 nM). 相似文献
13.
Jie Liu Qin Liu Xue Yang Shengtao Xu Hengyuan Zhang Renren Bai Hequan Yao Jieyun Jiang Mingqin Shen Xiaoming Wu Jinyi Xu 《Bioorganic & medicinal chemistry》2013,21(24):7742-7751
A series of novel 1,2,4-triazole bearing 5-substituted biphenyl-2-sulfonamide derivatives were designed and synthesized to develop new angiotensin II subtype 2 (AT2) receptor agonists as novel antihypertensive candidates. It was found that 14f (IC50 = 0.4 nM) and 15e (IC50 = 5.0 nM) displayed potent AT2 receptor affinity and selectivity in binding assays. Biological evaluation in vivo suggested that 14f is obviously superior to that of reference drug losartan in RHRs, and meanwhile, 14f has no significant impact on heart rate. The interesting activities of these compounds may make them promising candidates as antihypertensive agents. 相似文献
14.
Lorella Pasquinucci Orazio Prezzavento Agostino Marrazzo Emanuele Amata Simone Ronsisvalle Zafiroula Georgoussi Danai-Dionysia Fourla Giovanna M. Scoto Carmela Parenti Giuseppina Aricò Giuseppe Ronsisvalle 《Bioorganic & medicinal chemistry》2010,18(14):4975-4982
6,7-Benzomorphan derivatives, exhibiting different μ, δ, and κ receptor selectivity profiles depending on the N-substituent, represent a useful skeleton for the synthesis of new and better analgesic agents. In this work, an aromatic ring and/or alkyl residues have been used with an N-propanamide or N-acetamide spacer for the synthesis of a new series of 5,9-dimethyl-2′-hydroxy-6,7-benzomorphan derivatives (12–22). Data obtained by competition binding assays showed that the μ opioid receptor seems to prefer an interaction with the 6,7-benzomorphan ligands having an N-substituent with a propanamide spacer and less hindered amide. Highly stringent features are required for δ receptor interaction, while an N-acetamide spacer and/or bulkier amide could preferentially lead to κ receptor selectivity. In the propanamide series, compound 12 (named LP1) displayed high μ affinity (Ki = 0.83 nM), good δ affinity (Ki = 29 nM) and low affinity for the κ receptor (Ki = 110 nM), with a selectivity ratio δ/μ and κ/μ of 35.1 and 132.5, respectively. Further, in the adenylyl cyclase assay, LP1 displayed a μ/δ agonist profile, with IC50 values of 4.8 and 12 nM at the μ and δ receptors, respectively. The antinociceptive potency of LP1 in the tail-flick test after sc administration in rat was comparable with the potency of morphine (ED50 = 2.03 and 2.7 mg/kg, respectively), and was totally reversed by naloxone. LP1, possessing a μ/δ agonist profile, could represent a lead in further developing benzomorphan-based ligands with potent in vivo analgesic activity and a reduced tendency to induce side effects. 相似文献
15.
Aiko Nitta Yosuke Iura Hideki Inoue Ippei Sato Koichiro Morihira Hirokazu Kubota Tatsuaki Morokata Makoto Takeuchi Mitsuaki Ohta Shin-ichi Tsukamoto Takayuki Imaoka Toshiya Takahashi 《Bioorganic & medicinal chemistry letters》2012,22(22):6876-6881
Optimization starting with our lead compound 1 (IC50 = 4.9 nM) led to the identification of pyrrolidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea 32 (IC50 = 1.7 nM), a potent and orally active CCR3 antagonist. 相似文献
16.
Laszlo Revesz Achim Schlapbach Reiner Aichholz Janet Dawson Roland Feifel Stuart Hawtin Amanda Littlewood-Evans Guido Koch Markus Kroemer Henrik Möbitz Clemens Scheufler Juraj Velcicky Christine Huppertz 《Bioorganic & medicinal chemistry letters》2010,20(15):4719-4723
Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D–E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC50 <3 nM and inhibit the release of TNFα (IC50<0.3 μM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC50 = 0.05–0.23 μM), less potent in cells (IC50 <1.1 μM), but show good oral absorption. Compound 13E (100 mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score. 相似文献
17.
Soo Jeong Choi Myoung Ju Moon So Deok Lee Sang-Un Choi Sun-Young Han Yong-Chul Kim 《Bioorganic & medicinal chemistry letters》2010,20(6):2033-2037
Indirubin derivatives were identified as potent FLT3 tyrosine kinase inhibitors with anti-proliferative activity at acute myeloid leukemic cell lines, RS4;11 and MV4;11 which express FLT3-WT and FLT3-ITD mutation, respectively. Among several 5 and 5′-substituted indirubin derivatives, 5-fluoro analog, 13 exhibited potent inhibitory activity at FLT3 (IC50 = 15 nM) with more than 100-fold selectivity versus 6 other kinases and potent anti-proliferative effect for MV4;11 cells (IC50 = 72 nM) with 30-fold selectivity versus RS4;11 cells. Cell cycle analysis indicated that compound 13 induced cell cycle arrest at G0/G1 phase in MV4;11 cells. 相似文献
18.
《Bioorganic & medicinal chemistry letters》2014,24(3):954-962
The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50 = 19 and 15 nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50 = 121 and 99 nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described. 相似文献
19.
Jun Tang Karen E. Lackey Scott H. Dickerson 《Bioorganic & medicinal chemistry letters》2013,23(1):66-70
A series of novel, potent 4-aminothienopyridine B-Raf kinase inhibitors was designed and synthesized using knowledge-based design. Compounds 5f, and 6k exhibited not only excellent potency in both enzyme assay (IC50 = 5.1, 16.6 nM) and cellular assay (IC50 = 0.2, 0.2 μM), but also had an outstanding selectivity profile against other kinases. 相似文献
20.
Fumihito Muro Shin Iimura Yoshiyuki Yoneda Jun Chiba Toshiyuki Watanabe Masaki Setoguchi Gensuke Takayama Mika Yokoyama Tohru Takashi Atsushi Nakayama Nobuo Machinaga 《Bioorganic & medicinal chemistry》2009,17(3):1232-1243
During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease (3, IC50 = 19 nM) in VLA-4 inhibitory activity compared to 1 (IC50 = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC50 = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL = 3.3 ml/min/kg, F = 51%) in rats. 相似文献