共查询到20条相似文献,搜索用时 15 毫秒
1.
Sandham DA Aldcroft C Baettig U Barker L Beer D Bhalay G Brown Z Dubois G Budd D Bidlake L Campbell E Cox B Everatt B Harrison D Leblanc CJ Manini J Profit R Stringer R Thompson KS Turner KL Tweed MF Walker C Watson SJ Whitebread S Willis J Williams G Wilson C 《Bioorganic & medicinal chemistry letters》2007,17(15):4347-4350
High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat. 相似文献
2.
Erickson SD Banner B Berthel S Conde-Knape K Falcioni F Hakimi I Hennessy B Kester RF Kim K Ma C McComas W Mennona F Mischke S Orzechowski L Qian Y Salari H Tengi J Thakkar K Taub R Tilley JW Wang H 《Bioorganic & medicinal chemistry letters》2008,18(4):1402-1406
This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety. 相似文献
3.
Tabuchi S Itani H Sakata Y Oohashi H Satoh Y 《Bioorganic & medicinal chemistry letters》2002,12(8):1171-1175
Novel NPY-Y5 antagonist FR73966 was discovered by screening of our in-house chemical library. The analogues were prepared by application of parallel synthesis techniques. Some of the resulting 2-oxobenzothiazolin-3-acetic acid derivatives exhibited nanomolar binding affinity for human NPY-Y5 receptors. 相似文献
4.
Birkinshaw TN Teague SJ Beech C Bonnert RV Hill S Patel A Reakes S Sanganee H Dougall IG Phillips TT Salter S Schmidt J Arrowsmith EC Carrillo JJ Bell FM Paine SW Weaver R 《Bioorganic & medicinal chemistry letters》2006,16(16):4287-4290
Starting with the weak agonist indomethacin, a series of potent, selective CRTh2 (DP(2)) antagonists have been discovered as potential treatments for asthma, allergic rhinitis and other inflammatory diseases. 相似文献
5.
Luker T Bonnert R Brough S Cook AR Dickinson MR Dougall I Logan C Mohammed RT Paine S Sanganee HJ Sargent C Schmidt JA Teague S Thom S 《Bioorganic & medicinal chemistry letters》2011,21(21):6288-6292
Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22). 相似文献
6.
A new metabolite of the plant growth substance indole-3-acetic acid has been extracted from Zea mays seedlings and characterized as the 7'-O-beta-D-glucopyranoside of 7-hydroxy-2-oxindole-3-acetic acid. This compound was the major product formed from [5-3H] 2-oxindole-3-acetic acid, incubated with intact plants or root and coleoptile sections. Identification was by gas chromatography-mass spectrometry of the trimethylsilyl derivative and by analysis of the hydrolysis products. A synthesis is reported for 7-hydroxy-2-oxindole-3-acetic acid. These results and prior work demonstrate the following catabolic route for indole-3-acetic acid in Zea: indole-3-acetic acid----2-oxindole-3-acetic acid----7-hydroxy-2-oxindole-3-acetic acid----7-hydroxy-2-oxindole-3-acetic acid glucoside. 相似文献
7.
Graeme Semple Britt-Marie Andersson Vijay Chhajlani Jennie Georgsson Magnus Johansson Marcel Lindschoten Fritof Pontén Asa Rosenquist Henrik S?rensen Lars Swanson Marianne Swanson 《Bioorganic & medicinal chemistry letters》2002,12(2):197-200
A new series of 3-aryl pyridone based kappa opioid receptor agonists was designed and synthesised, based on an understanding of the classical kappa opioid receptor pharmacophore. The most potent of the new compounds were comparable to U-69,593 in receptor affinity, selectivity and functional agonist effect at the cloned human kappa opioid receptor. 相似文献
8.
The SmI(2)-promoted three-component coupling reaction of thiophene-2-carboxylate, indole-2-carbaldehyde and acetophenone provides an expedient route to a series of tetracyclic carbazolothiophene compounds bearing the indole and thiophene rings. Among these samples, 9-benzyl-4-methyl-4-(4-hydroxyphenyl)-10-oxo-4,10-dihydrocarbazolo[2,3-b]thiophene-2-carboxylic acid (18) shows the most potent inhibition against the endothelin-1 induced increase of intracellular calcium ion concentration. 相似文献
9.
Palani A Dugar S Clader JW Greenlee WJ Ruperto V Duffy RA Lachowicz JE 《Bioorganic & medicinal chemistry letters》2004,14(7):1791-1794
Low molecular weight amide derivatives were synthesized and evaluated as M(2) receptor antagonists for the treatment of Alzheimer's disease. Isopropyl amides 19 and 31 are highly potent, selective and low molecular weight M(2) receptor antagonists with structural features different from our clinical candidate 1. 相似文献
10.
Bernard R. Neustadt Hong Liu Jinsong Hao William J. Greenlee Andrew W. Stamford Carolyn Foster Leyla Arik Jean Lachowicz Hongtao Zhang Rosalia Bertorelli Silva Fredduzzi Geoffrey Varty Mary Cohen-Williams Kwokei Ng 《Bioorganic & medicinal chemistry letters》2009,19(3):967-971
Antagonism of the adenosine A2a receptor offers great promise in the treatment of Parkinson’s disease. In the course of exploring pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonists, which led to clinical candidate SCH 420814, we prepared 1,2,4-triazolo[1,5-c]pyrimidines with potent and selective (vs A1) A2a antagonist activity, including oral activity in the rat haloperidol-induced catalepsy model. Structure–activity relationships and plasma levels are described for this series. 相似文献
11.
Oost T Backfisch G Bhowmik S van Gaalen MM Geneste H Hornberger W Lubisch W Netz A Unger L Wernet W 《Bioorganic & medicinal chemistry letters》2011,21(12):3828-3831
Herein we report the discovery of a novel series of vasopressin 1b (V1b) receptor antagonists, starting from potent but metabolically labile oxindole SSR149415. Masking the proline N,N-dimethyl amide moiety as an oxazole and attaching a benzylic amine moiety to the northern phenyl ring resulted in potent and selective V1b receptor antagonists with improved metabolic stability and improved pharmacokinetic properties in rat. Compound 18c was found to be efficacious in a rat model of anti-depressant activity. 相似文献
12.
Harris JM Neustadt BR Zhang H Lachowicz J Cohen-Williams M Varty G Hao J Stamford AW 《Bioorganic & medicinal chemistry letters》2011,21(8):2497-2501
Antagonism of the adenosine A2A receptor affords a possible treatment of Parkinson’s disease. In the course of investigating pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonists, we prepared [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones with potent and selective (vs A1) A2A antagonist activity. Structure-activity relationships are described for this series. 相似文献
13.
Borza I Kolok S Galgóczy K Gere A Horváth C Farkas S Greiner I Domány G 《Bioorganic & medicinal chemistry letters》2007,17(2):406-409
A novel series of kynurenic acid amides, ring-enlarged derivatives of indole-2-carboxamides, was prepared and identified as in vivo active NR2B subtype selective NMDA receptor antagonists. The synthesis and SAR studies are discussed. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2014,24(14):3043-3045
A series of amides were synthesized by condensation of theophylline-7-acetic acid and eight commercially available amino acid methyl ester hydrochlorides. Consecutive hydrolysis of six of the amido-esters resulted in the formation of corresponding amido-acids. The newly synthesized compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. The activity varied depending on the amino acid fragments and in seven cases exerted excellent values with MICs 0.46–0.26 μM. Assessment of the cytotoxicity revealed that the compounds were not cytotoxic against the human embryonal kidney cell line HEK-293T. The theophylline-7-acetamides containing amino acid moieties appear to be promising lead compounds for the development of antimycobacterial agents. 相似文献
15.
Masayuki Nakamura Hideki Kurihara Gentaroh Suzuki Morihiro Mitsuya Mitsuru Ohkubo Hisashi Ohta 《Bioorganic & medicinal chemistry letters》2010,20(2):726-729
This Letter describes the synthesis and evaluation of mGluR7 antagonists in the isoxazolopyridone series. In the course of modification in this class, novel solid support synthesis of the isoxazolopyridone scaffold was developed. Subsequent chemical modification led to the identification of several potent derivatives with improved physicochemical properties compared to a hit compound 1. Among these, 2 showed good oral bioavailability and brain penetrability, suggesting that 2 may be useful for in vivo study to elucidate the role of mGluR7. 相似文献
16.
Ng RA Guan J Alford VC Lanter JC Allan GF Sbriscia T Linton O Lundeen SG Sui Z 《Bioorganic & medicinal chemistry letters》2007,17(3):784-788
The synthesis and in vivo SAR of 5,6-dichloro-benzimidazole derivatives as novel selective androgen receptor antagonists are described. During screening of 2-alkyl benzimidazoles, it was found that a trifluoromethyl group greatly enhances antagonist activity in the prostate. Benzimidazole 1 is a potent AR antagonist in the rat prostate (ID50 = 0.15 mg/day). 相似文献
17.
Luker T Bonnert R Schmidt J Sargent C Paine SW Thom S Pairaudeau G Patel A Mohammed R Akam E Dougall I Davis AM Abbott P Brough S Millichip I McInally T 《Bioorganic & medicinal chemistry letters》2011,21(12):3616-3621
A novel series of biaryl phenoxyacetic acids was discovered as potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A hit compound 4 was discovered from high throughput screening. Modulation of multiple aryl substituents afforded both agonists and antagonists, with small changes often reversing the mode of action. Understanding the complex SAR allowed design of potent antagonists such as potential candidate 34. 相似文献
18.
Christine Yang Hong C. Shen Zhicai Wu Hong D. Chu Jason M. Cox Jaume Balsells Alejandro Crespo Patricia Brown Beata Zamlynny Judyann Wiltsie Joseph Clemas Jack Gibson Lisa Contino JeanMarie Lisnock Gaochao Zhou Margarita Garcia-Calvo Tom Bateman Ling Xu Peter Sinclair 《Bioorganic & medicinal chemistry letters》2013,23(15):4388-4392
Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR) antagonists. Structure–activity relationship (SAR) studies were focused on improving the potency and microsomal stability. Selected compounds demonstrated excellent MR activity, reasonable nuclear hormone receptor selectivity, and acceptable rat pharmacokinetics. 相似文献
19.
Jason W. Skudlarek Christina N. DiMarco Kerim Babaoglu Anthony J. Roecker Joseph G. Bruno Mark A. Pausch Julie A. OBrien Tamara D. Cabalu Joanne Stevens Joseph Brunner Pamela L. Tannenbaum W. Peter Wuelfing Susan L. Garson Steven V. Fox Alan T. Savitz Charles M. Harrell Anthony L. Gotter Christopher J. Winrow Paul J. Coleman 《Bioorganic & medicinal chemistry letters》2017,27(6):1364-1370
In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX2R subtype and culminating in the discovery of 23, a highly potent, OX2R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX1R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed. 相似文献
20.
Naganawa A Matsui T Ima M Yoshida K Tsuruta H Yamamoto S Yamamoto H Okada H Maruyama T Nakai H Kondo K Toda M 《Bioorganic & medicinal chemistry》2006,14(23):7774-7789
A series of 4-[(2-{isobutyl[(5-methyl-2-furyl)sulfonyl]amino}phenoxy)methyl]benzoic acids and 4-({2-[isobutyl(1,3-thiazol-2-ylsulfonyl)amino]phenoxy}methyl)benzoic acids were synthesized and evaluated for their EP receptor affinities and EP1 receptor antagonist activities. Further structural optimization was carried out to reduce inhibitory activity against hepatic cytochrome P450 isozymes, which could represent a harmful potential drug interaction. Selected compounds were also evaluated for their binding affinities to hTP, hDP, mFP, and hIP, and for their hEP1 receptor antagonist activities. The results of structure-activity relationship studies are also presented. 相似文献