共查询到20条相似文献,搜索用时 62 毫秒
1.
Ronald C. Bernotas Schuyler Antane Rajesh Shenoy Van-Duc Le Ping Chen Boyd L. Harrison Albert J. Robichaud Guo Ming Zhang Deborah Smith Lee E. Schechter 《Bioorganic & medicinal chemistry letters》2010,20(5):1657-1660
Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT6 receptor ligands, based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds had good 5-HT6 binding affinity with Ki values <10 nM. Depending on substitution, both agonists (e.g., 6o: EC50 = 60 nM, Emax = 70%) and antagonists (6y: IC50 = 17 nM, Imax = 86%) were identified in a 5-HT6 adenylyl cyclase assay. 相似文献
2.
《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
3.
Jian Liu Shuwen He Tianying Jian Peter H. Dobbelaar Iyassu K. Sebhat Linus S. Lin Allan Goodman Cheng Guo Peter R. Guzzo Mark Hadden Alan J. Henderson Kevin Pattamana Megan Ruenz Bruce J Sargent Brian Swenson Larry Yet Constantin Tamvakopoulos Qianping Peng Jie Pan Yanqing Kan Ravi P. Nargund 《Bioorganic & medicinal chemistry letters》2010,20(7):2074-2077
This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl)phenyl]ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC50 = 18 nM, hBRS-3) and functional agonist activity (EC50 = 47 nM, 99% activation). After oral administration, compound 9 had sufficient exposure in diet induced obese mice to demonstrate efficacy in lowering food intake and body weight via BRS-3 activation. 相似文献
4.
《Bioorganic & medicinal chemistry》2014,22(6):1929-1937
The new series of 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles, possessing C-3 thio, alkylthio and ethoxy substituents, and 2-amino-5-(2-phenoxybenzyl)-1,3,4-oxadiazoles were designed and synthesized as novel benzodiazepine analogues. Most of them revealed similar to superior binding affinity to the GABAA/benzodiazepine receptor complex, relative to diazepam as the reference drug. Among them, 5-(4-chloro-2-(2-fluorophenoxy)benzyl)-3-benzylthio-4H-1,2,4-triazole (8l) showed the highest affinity (IC50 = 0.892 nM) relative to diazepam (IC50 = 2.857 nM) and also showed the most increase in pentylenetetrazole-induced seizure threshold relative to diazepam as the reference drug. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2014,24(15):3412-3418
The synthesis and structure–activity relationships of novel 4-(4′-fluorophenyl)imidazoles as selective p38α MAPK, CK1δ and JAK2 inhibitors with improved water solubility are described. Microwave-assisted multicomponent reactions afforded 4-fluorophenyl-2,5-disubstituted imidazoles. Carboxylate and phosphonate groups were introduced via ‘click’ reactions. The kinase selectivity was influenced by the heteroaryl group at imidazole C-5 and the position of a carboxylic acid or tetrazole at imidazole C-2. For example, pyrimidines 15 and 34 inhibited p38α MAPK with IC50 = 250 nM and 96 nM, respectively. Pyridine 3 gave CK1δ inhibition with IC50 = 89 nM and pyridin-2-one 31 gave JAK2 inhibition with IC50 = 62 nM. 相似文献
6.
Ahmed S. Aboraia Sook Wah Yee Mohamed Sayed Gomaa Nikhil Shah Anna C. Robotham Bart Makowski David Prosser Andrea Brancale Glenville Jones Claire Simons 《Bioorganic & medicinal chemistry》2010,18(14):4939-4946
A series of N-(2-(1H-imidazol-1-yl)-2-phenylethyl)arylamides were prepared, using an efficient three- to five-step synthesis, and evaluated for their inhibitory activity against human cytochrome P450C24A1 (CYP24A1) hydroxylase. Inhibition ranged from IC50 0.3–72 μM compared with the standard ketoconazole IC50 0.52 μM, with the styryl derivative (11c) displaying enhanced activity (IC50 = 0.3 μM) compared with the standard, providing a useful preliminary lead for drug development. 相似文献
7.
Janet Gunzner-Toste Guiling Zhao Paul Bauer Timm Baumeister Alexandre J. Buckmelter Maureen Caligiuri Karl H. Clodfelter Bang Fu Bingsong Han Yen-Ching Ho Nikolai Kley Xiaorong Liang Bianca M. Liederer Jian Lin Sophie Mukadam Thomas O’Brien Angela Oh Dominic J. Reynolds Peter S. Dragovich 《Bioorganic & medicinal chemistry letters》2013,23(12):3531-3538
Potent, reversible inhibition of the cytochrome P450 CYP2C9 isoform was observed in a series of urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. This unwanted property was successfully removed from the described inhibitors through a combination of structure-based design and medicinal chemistry activities. An optimized compound which did not inhibit CYP2C9 exhibited potent anti-NAMPT activity (17; BC NAMPT IC50 = 3 nM; A2780 antiproliferative IC50 = 70 nM), good mouse PK properties, and was efficacious in an A2780 mouse xenograft model. The crystal structure of this compound in complex with the NAMPT protein is also described. 相似文献
8.
《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
9.
Ronald C. Bernotas David H. Kaufman Robert R. Singhaus John Ullrich Rayomand Unwalla Elaine Quinet Ponnal Nambi Anna Wilhelmsson Annika Goos-Nilsson Jay Wrobel 《Bioorganic & medicinal chemistry》2009,17(23):8086-8092
A series of 4-(3-aryloxyaryl)quinolines with alcohol substituents on the terminal aryl ring was prepared as potential LXR agonists, in which an alcohol group replaced an amide in previously reported amide analogs. High affinity LXR ligands with excellent agonist potency and efficacy in a functional model of LXR activity were identified, demonstrating that alcohols can substitute for amides while retaining LXR activity. The most potent compound was 5b which had an IC50 = 3.3 nM for LXRβ binding and EC50 = 12 nM (122% efficacy relative to T0901317) in an ABCA1 mRNA induction assay in J774 mouse cells. 相似文献
10.
《Bioorganic & medicinal chemistry》2016,24(7):1513-1519
Negative allosteric modulators (NAMs) of GluN2B-containing NMDARs provide pharmacological tools for the treatment of chronic neurodegenerative diseases. Novel NAMs have been designed on the basis of computational studies focused on the ‘hit compound’ 3. This series of indoles has been tested in competition assay. Compounds 16 and 17 were the most active ligands (IC50 values of 83 nM and 71 nM, respectively) and they showed a potency close to that of reference compounds ifenprodil (1, IC50 = 47 nM) and 3 (IC50 = 25 nM). Furthermore, docking studies have been performed for active ligand 16 and the results were in a good agreement with biological data. 相似文献
11.
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
12.
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
13.
Jeffrey J. Letourneau Christopher M. Riviello Hong Li Andrew G. Cole Koc-Kan Ho Heather A. Zanetakos Hema Desai Jiuqiao Zhao Douglas S. Auld Susan E. Napier Fiona J. Thomson Katharine A. Goan J. Richard Morphy Michael H.J. Ohlmeyer Maria L. Webb 《Bioorganic & medicinal chemistry letters》2010,20(18):5394-5397
The discovery, synthesis, and preliminary structure–activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million-member compound collection, prepared using ECLiPS? technology, had good activity in a V3 binding assay (IC50 = 0.20 μM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC50 = 0.31 μM) and 24 (IC50 = 0.12 μM) with improved drug-like characteristics. 相似文献
14.
Robert J. Cherney Ruowei Mo Dayton T. Meyer Matthew E. Voss Yvonne C. Lo Gengjie Yang Persymphonie B. Miller Peggy A. Scherle Andrew J. Tebben Percy H. Carter Carl P. Decicco 《Bioorganic & medicinal chemistry letters》2009,19(13):3418-3422
Potent sulfone-containing di- and trisubstituted cyclohexanes were synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the trisubstituted derivative 54, which exhibited excellent binding (CCR2 IC50 = 1.3 nM) and functional antagonism (calcium flux IC50 = 0.5 nM and chemotaxis IC50 = 0.2 nM). The superiority of the trisubstituted scaffold was rationalized to be the result of a conformational rigidification, which provided insight into the bioactive conformation of this chemotype. 相似文献
15.
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
16.
Maria João Matos Dolores Viña Patricia Janeiro Fernanda Borges Lourdes Santana Eugenio Uriarte 《Bioorganic & medicinal chemistry letters》2010,20(17):5157-5160
With the aim to find out the structural features for the MAO inhibitory activity and selectivity, in the present communication we report the synthesis and pharmacological evaluation of a new series of bromo-6-methyl-3-phenylcoumarin derivatives (with bromo atom in both different benzene rings of the skeleton) with and without different number of methoxy substituent at the 3-phenyl ring. The methoxy substituents were introduced, in this new scaffold, in the meta and/or para positions of the 3-phenyl ring. The synthesized compounds 3–7 were evaluated as MAO-A and B inhibitors using R-(?)-deprenyl (selegiline) and iproniazide as reference inhibitors, showing, most of them, MAO-B inhibitory activities in the low nanomolar range. Compounds 4 (IC50 = 11.05 nM), 5 (IC50 = 3.23 nM) and 6 (IC50 = 7.12 nM) show higher activity than selegiline (IC50 = 19.60 nM) and higher MAO-B selectivity, with more than 9050-fold, 30,960-fold and 14,045-fold inhibition levels, with respect to the MAO-A isoform. 相似文献
17.
Teng-Kuang Yeh Ting-Yueh Tsai Tsu Hsu Jai-Hong Cheng Xin Chen Jen-Shin Song Horng-Shing Shy Mei-Chun Chiou Chia-Hui Chien Ya-Ju Tseng Chung-Yu Huang Kai-Chia Yeh Yu-Lin Huang Chih-Hsiang Huang Yu-Wen Huang Min-Hsien Wang Hung-Kuan Tang Yu-Sheng Chao Chiung-Tong Chen Weir-Torn Jiaang 《Bioorganic & medicinal chemistry letters》2010,20(12):3596-3600
A series of 2-[3-[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-based DPP-IV inhibitors with various monocyclic amines were synthesized. The structure–activity relationships (SAR) led to the discovery of potent DPP-IV inhibitors, having IC50 values of <100 nM with excellent selectivity over the closely related enzymes, DPP-II, DPP8, DPP9 and FAP (IC50 > 20 μM). Of these compounds, the analogues 12a, 12h and 12i exhibited a long-lasting ex vivo DPP-IV inhibition in rats. 相似文献
18.
《Bioorganic & medicinal chemistry letters》2014,24(2):591-594
Forty four di- or trisubstituted novel isatin derivatives were designed and synthesized in 5–6 steps in 25–45% overall yields. Their structures were confirmed by 1H NMR and 13C NMR as well as LC–MS. The anticancer activity of these new isatin derivatives against three human tumor cell lines, K562, HepG2 and HT-29, were evaluated by MTT assay in vitro. SAR studies suggested that the combination of 1-benzyl and 5-[trans-2-(methoxycarbonyl)ethen-1-yl] substitution greatly enhance their cytotoxic activity, whereas an intact carbonyl functionality on C-3 as present in the parent ring is required to such a potency. This study leads to the identification of two highly active molecules, compounds 2h (IC50 = 3 nM) and 2k (IC50 = 6 nM), against human leukemia K562 cells. 相似文献
19.
Yan Shi Chi Li Stephen P. O’Connor Jing Zhang Mengxiao Shi Sharon N. Bisaha Ying Wang Doree Sitkoff Andrew T. Pudzianowski Christine Huang Herbert E. Klei Kevin Kish Joseph Yanchunas Eddie C.-K. Liu Karen S. Hartl Steve M. Seiler Thomas E. Steinbacher William A. Schumacher Karnail S. Atwal Philip D. Stein 《Bioorganic & medicinal chemistry letters》2009,19(24):6882-6889
We report the design and synthesis of a novel class of N,N′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure–activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC50 = 4 nM, EC2×PT = 7 μM). However, the potent CYP3A4 inhibition activity (IC50 = 0.3 μM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC50 = 9 nM, EC2×PT = 2.5 μM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. 相似文献
20.
Hamid Nadri Morteza Pirali-Hamedani Maryam Shekarchi Mohammad Abdollahi Vahid Sheibani Massoud Amanlou Abbas Shafiee Alireza Foroumadi 《Bioorganic & medicinal chemistry》2010,18(17):6360-6366
A novel series of benzofuranone-ylidene-methyl benzylpyridinium derivatives (6a–u) were synthesized as acetylcholinesterase inhibitors. The anticholinesterase activity of synthesized compounds was measured using colorimetric Ellman’s method. It was revealed that some synthesized compounds exhibited high anticholinesterase activity, among them compound 6b was the most active compound (IC50 = 10 ± 6.87 nM). 相似文献