共查询到20条相似文献,搜索用时 31 毫秒
1.
Paige E. Mahaney Callain Y. Kim Richard D. Coghlan Stephen T. Cohn Gavin D. Heffernan Christine A. Huselton Eugene A. Terefenko An T. Vu Puwen Zhang Kevin D. Burroughs Scott A. Cosmi Jenifer A. Bray Grace H. Johnston Darlene C. Deecher Eugene J. Trybulski 《Bioorganic & medicinal chemistry letters》2009,19(19):5807-5810
The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as monoamine reuptake inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC50 value of 4 nM while exhibiting 86-fold selectivity over the serotonin transporter. 相似文献
2.
Tomoya Shiro Keisuke Kakiguchi Hirotada Takahashi Hidetaka Nagata Masanori Tobe 《Bioorganic & medicinal chemistry》2013,21(11):2868-2878
To identify compounds with strong mPGES-1 inhibitory activity and clear in vitro ADME profile, we optimized the lead compound 1 by carrying our substitutions at the C(7)- and C(8)-positions. Replacement of the bromine atom of 1 with various substituents led to identification of the phenyl group as the best C(7)-substituent giving strong inhibitory activity with good in vitro ADME profile. Further SAR examination on both the C(2)- and the C(7)-phenyl groups provided compound 39 as the best candidate for further development. Compound 39 exhibited strong mPGES-1 inhibitory activity (IC50 = 4.1 nM), potent cell-based functional activity (IC50 = 33 nM) with good mPGES-1 selectivity (over 700-fold), excellent in vitro ADME profile, and good oral absorption in rat PK study. 相似文献
3.
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
4.
Renee Aspiotis Denis Deschênes Daniel Dubé Yves Girard Zheng Huang France Laliberté Susana Liu Robert Papp Donald W. Nicholson Robert N. Young 《Bioorganic & medicinal chemistry letters》2010,20(18):5502-5505
The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC50 = 0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized. 相似文献
5.
Zoran Rankovic Jiaqiang Cai Jennifer Kerr Xavier Fradera John Robinson Ashvin Mistry Emma Hamilton George McGarry Fiona Andrews Wilson Caulfield Iain Cumming Maureen Dempster John Waller Paul Scullion Iain Martin Ann Mitchell Clive Long Mark Baugh Paul Westwood Emma Kinghorn Eric Nicolai 《Bioorganic & medicinal chemistry letters》2010,20(5):1524-1527
Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC50 = 4 nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%. 相似文献
6.
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
7.
Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors
Yan Shi Jing Zhang Mengxiao Shi Stephen P. O’Connor Sharon N. Bisaha Chi Li Doree Sitkoff Andrew T. Pudzianowski Saeho Chong 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(15):4034-4041
The N,N′-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, Ki = 6.5 nM, EC2xPT = 32 μM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand–protein interactions are discussed. 相似文献
8.
《Bioorganic & medicinal chemistry》2016,24(21):5495-5504
The clinical selective estrogen receptor modulator tamoxifen is also a modest inhibitor of protein kinase C, a target implicated in several untreatable brain diseases such as amphetamine abuse. This inhibition and tamoxifen’s ability to cross the blood brain barrier make it an attractive scaffold to conduct further SAR studies toward uncovering effective therapies for such diseases. Utilizing the known compound 6a as a starting template and guided by computational tools to derive physicochemical properties known to be important for CNS permeable drugs, the design and synthesis of a small series of novel triarylacrylonitrile analogues have been carried out providing compounds with enhanced potency and selectivity for PKC over the estrogen receptor relative to tamoxifen. Shortened synthetic routes compared to classical procedures have been developed for analogues incorporating a β-phenyl ring, which involve installing dialkylaminoalkoxy side chains first off the α and/or α′ rings of a precursor benzophenone and then condensing the resultant ketones with phenylacetonitrile anion. A second novel, efficient and versatile route utilizing Suzuki chemistry has also been developed, which will allow for the introduction of a wide range of β-aryl or β-heteroaryl moieties and side-chain substituents onto the acrylonitrile core. For analogues possessing a single side chain off the α- or α′-ring, novel 2D NMR experiments have been carried out that allow for unambiguous assignment of E- and Z-stereochemistry. From the SAR analysis, one compound, 6c, shows markedly increased potency and selectivity for inhibiting PKC with an IC50 of 80 nM for inhibition of PKC protein substrate and >10 μM for binding to the estrogen receptor α (tamoxifen IC50 = 20 μM and 222 nM, respectively). The data on 6c provide support for further exploration of PKC as a druggable target for the treatment of amphetamine abuse. 相似文献
9.
Leyi Gong Xiaochun Han Tania Silva Yun-Chou Tan Bindu Goyal Parch Tivitmahaisoon Alejandra Trejo Wylie Palmer Heather Hogg Alam Jahagir Muzaffar Alam Paul Wagner Karin Stein Lubov Filonova Brad Loe Ferenc Makra David Rotstein Lubica Rapatova David Goldstein 《Bioorganic & medicinal chemistry letters》2013,23(12):3565-3569
A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties. 相似文献
10.
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
11.
Zhongli Gao William J. Hurst Werngard Czechtizky Dominique Francon Guy Griebel Raisa Nagorny Philippe Pichat Lothar Schwink Siegfried Stengelin James A. Hendrix Pascal G. George 《Bioorganic & medicinal chemistry letters》2013,23(22):6141-6145
Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), Ki = 8.6 nM, rhesus monkey (rh-H3R), Ki = 1.2 nM, and rat (r-H3R), Ki = 16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep–wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep–wake disorders. 相似文献
12.
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
13.
Andrew M.K. Pennell James B. Aggen Subhabrata Sen Wei Chen Yuan Xu Edward Sullivan Lianfa Li Kevin Greenman Trevor Charvat Derek Hansen Daniel J. Dairaghi J.J. Kim Wright Penglie Zhang 《Bioorganic & medicinal chemistry letters》2013,23(5):1228-1231
A novel series of CCR1 antagonists based on the 1-(4-phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone scaffold was identified by screening a compound library utilizing CCR1-expressing human THP-1 cells. SAR studies led to the discovery of the highly potent and selective CCR1 antagonist 14 (CCR1 binding IC50 = 4 nM using [125I]-CCL3 as the chemokine ligand). Compound 14 displayed promising pharmacokinetic and toxicological profiles in preclinical species. 相似文献
14.
Torsten Steinmetzer Daniel Dönnecke Martin Korsonewski Claudia Neuwirth Peter Steinmetzer Alexander Schulze Sebastian Martin Saupe Andrea Schweinitz 《Bioorganic & medicinal chemistry letters》2009,19(1):67-73
Replacement of the N-terminal β-alanyl-amide moiety in previously identified matriptase inhibitors by non-charged aryl groups caused a slightly decreased potency and partially reduced selectivity, especially towards thrombin. However, some of these analogues are still potent matriptase inhibitors with Ki-values <10 nM. In contrast, improved activity was observed for newly designed tribasic analogues, especially for compound 21, which inhibits matriptase with an Ki-value of 80 pM. 相似文献
15.
Jeroen C. Verheijen Ker Yu Lourdes Toral-Barza Irwin Hollander Arie Zask 《Bioorganic & medicinal chemistry letters》2010,20(1):375-379
2-Aryl-4-morpholinothieno[3,2-d]pyrimidines are known PI3K inhibitors. This class of compounds also potently inhibited the homologous enzyme mTOR. Replacement of the morpholine group in these compounds with an 8-oxa-3-azabicyclo[3.2.1]octane group led to mTOR inhibitors with selectivity over PI3K. Optimization of the 2-aryl substituent led to the discovery of 2-(4-ureidophenyl)-thienopyrimidines as highly potent (IC50 <1 nM) mTOR inhibitors with excellent selectivity (up to >1000-fold) over PI3K and good potency in a cellular proliferation assay (IC50 <50 nM). 相似文献
16.
《Bioorganic & medicinal chemistry letters》2014,24(9):2094-2097
Lactam and oxazolidinone derived potent 5-hydroxytryptamine 6 (5-HT6) receptor antagonists have been disclosed. One potent member from the lactam series, racemic compound 14 (Ki of 2.6 nM in binding assay, IC50 of 15 nM in functional cAMP antagonism assay) was separated into corresponding enantiomers that displayed the effect of chirality on binding potency (Ki of 1.6 nM and 3000 nM, respectively). The potent enantiomer displayed an IC50 of 8 nM in cAMP antagonism assay, selectivity against a number of family members as well as brain permeability in rats after 6 h post oral administration. 相似文献
17.
《Bioorganic & medicinal chemistry letters》2014,24(8):1958-1962
As a continuous research for discovery of new COX-2 inhibitors, we present the simple chemical synthesis, in vitro biological screening, and molecular docking study of 1H-pyrrole-2,5-dione derivatives. New synthetic compounds were evaluated for the inhibitory activities on LPS-induced PGE2 production in RAW 264.7 macrophage cells as well as the COX-1 and COX-2 inhibitory potency. Among them, compound 9d (MPO-0029) was identified as more potent and selective COX-2 inhibitor [PGE2 IC50 = 8.7 nM, COX-2 IC50 = 6.0 nM; COX-2 selectivity index (SI) = >168] than celecoxib. Molecular docking experiments were further performed against COX-2 and COX-1 isozymes to determine their probable binding models. Results of molecular docking studies revealed that compound 9d (MPO-0029) has stronger binding interaction with COX-2 than with COX-1 isozyme, and provided successfully complementary theoretical support for the obtained experimental biological data. 相似文献
18.
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
19.
Leyi Gong Don Hirschfeld Yun-Chou Tan J. Heather Hogg Gary Peltz Zafrira Avnur Pete Dunten 《Bioorganic & medicinal chemistry letters》2010,20(5):1693-1696
Here we report on the discovery of a series of maleimides which have high potency and good selectivity for GSK-3β. The incorporation of polar groups afforded compounds with good bioavailability. The most potent compound 34 has an IC50 of 0.6 nM for GSK-3β, over 100-fold selectivity against a panel of other kinases, and shows efficacy in rat osteoporosis models. The X-ray structure of GSK-3β protein with 34 bound revealed the binding mode of the template and provided insights for future optimization opportunities. 相似文献
20.
Qingyian Liu Wenyuan Qian Aiwen Li Kaustav Biswas Jian Jeffrey Chen Christopher Fotsch Nianhe Han Chester Yuan Leyla Arik Gloria Biddlecome Eileen Johnson Gondi Kumar Dianna Lester-Zeiner Gordon Y. Ng Randall W. Hungate Benny C. Askew 《Bioorganic & medicinal chemistry letters》2010,20(15):4593-4597
The bradykinin B1 receptor has been shown to mediate pain response and is rapidly induced upon injury. Blocking this receptor may provide a promising treatment for inflammation and pain. We previously reported tetralin benzyl amines as potent B1 antagonists. Here we describe the synthesis and SAR of B1 receptor antagonists with homobenzylic amines. The SAR of different linkers led to the discovery of tetralin allylic amines as potent and selective B1 receptor antagonists (hB1 IC50 = 1.3 nM for compound 16). Some of these compounds showed modest oral bioavailability in rats. 相似文献