共查询到20条相似文献,搜索用时 0 毫秒
1.
Tehrani LR Smith ND Huang D Poon SF Roppe JR Seiders TJ Chapman DF Chung J Cramer M Cosford ND 《Bioorganic & medicinal chemistry letters》2005,15(22):5061-5064
Structure-activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery that small, non-hydrogen bond donor substituents at the 3-position led to a substantial increase in in vitro potency. In particular, 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (7) is a highly potent and selective mGlu5 receptor antagonist with good rat pharmacokinetics, brain penetration, and in vivo receptor occupancy. 相似文献
2.
Mizutani T Nagase T Ito S Miyamoto Y Tanaka T Takenaga N Tokita S Sato N 《Bioorganic & medicinal chemistry letters》2008,18(23):6041-6045
Novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives were identified as potent human H(3) receptor inverse agonists. After systematic modification of lead 5a, the potent and selective analog 5r was identified. Elimination of hERG K(+) channel and human alpha(1A)-adrenoceptor activities is the main focus of the present study. 相似文献
3.
Novel histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine scaffold
Vaccaro WD Sher R Berlin M Shih NY Aslanian R Schwerdt JH McCormick KD Piwinski JJ West RE Anthes JC Williams SM Wu RL She HS Rivelli MA Mutter JC Corboz MR Hey JA Favreau L 《Bioorganic & medicinal chemistry letters》2006,16(2):395-399
We report the discovery of novel histamine H(3) receptor antagonists based on 4-[(1H-imidazol-4-yl)methyl]piperidine. The most potent compounds in the series (e.g., 7) result from the attachment of a substituted aniline amide to the main pharmacophore piperidine via a two-methylene linker. 相似文献
4.
Matthew J Tozer Ildiko M Buck Tracey Cooke S Barret Kalindjian Michael J Pether Katherine I M Steel 《Bioorganic & medicinal chemistry》2002,10(2):425-432
omega-(1H-Imidazol-4-yl)alkane-1-sulfonamides were prepared and found to be potent histamine H(3) receptor antagonists. High receptor affinity and a low difference in the data between the bioassays were achieved with 5-(1H-imidazol-4-yl)pentane-1-sulfonic acid 4-chlorobenzylamide (16). Good in vitro profiles were also obtained for 2-hydroxysulfonamide and vinylsulfonamide analogues. This complements and completes the existing set of imidazole-based sulfonamides and sulfamides. 相似文献
5.
Cole DC Ellingboe JW Lennox WJ Mazandarani H Smith DL Stock JR Zhang G Zhou P Schechter LE 《Bioorganic & medicinal chemistry letters》2005,15(2):379-383
A series of N(1)-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)indole derivatives was designed and synthesized. These compounds were shown to have high affinity for the 5-HT(6) receptor. Two analogs, 4-[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-1-sulfonyl]-phenylamine 15g and 4-[3-(1,2,3,6-tetrahydropyridin-4-yl)-5-methoxy-1H-indole-1-sulfonyl]-phenylamine 15y, had 0.4 and 3.0 nM affinity, respectively, and antagonized the production of adenylate cyclase at sub-nanomolar concentrations. 相似文献
6.
Stock N Volkots D Stebbins K Broadhead A Stearns B Roppe J Parr T Baccei C Bain G Chapman C Correa L Darlington J King C Lee C Lorrain DS Prodanovich P Santini A Evans JF Hutchinson JH Prasit P 《Bioorganic & medicinal chemistry letters》2011,21(3):1036-1040
Compound 21 (AM432) was identified as a potent and selective antagonist of the DP2 receptor (CRTH2). Modification of a bi-aryl core identified a series of tri-aryl antagonists of which compound 21 proved a viable clinical candidate. AM432 shows excellent potency in a human whole blood eosinophil shape change assay with prolonged incubation, a comparatively long off-rate from the DP2 receptor, excellent pharmacokinetics in dog and in vivo activity in two mouse models of inflammatory disease after oral dosing. 相似文献
7.
Emily M. Stocking Leah Aluisio John R. Atack Pascal Bonaventure Nicholas I. Carruthers Christine Dugovic Anita Everson Ian Fraser Xiaohui Jiang Perry Leung Brian Lord Kiev S. Ly Kirsten L. Morton Diane Nepomuceno Chandravadan R. Shah Jonathan Shelton Akinola Soyode-Johnson Michael A. Letavic 《Bioorganic & medicinal chemistry letters》2010,20(9):2755-2760
Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H3 receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H3 receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate. 相似文献
8.
《Bioorganic & medicinal chemistry》2014,22(19):5428-5445
In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects. 相似文献
9.
Ronald C. Bernotas Schuyler A. Antane Steven E. Lenicek Simon N. Haydar Albert J. Robichaud Boyd L. Harrison Guo Ming Zhang Deborah Smith Joseph Coupet Lee E. Schechter 《Bioorganic & medicinal chemistry letters》2009,19(24):6935-6938
1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines were prepared. Binding assays indicated they are 5-HT6 receptor ligands, among which 6f and 6g showed high affinity for 5-HT6 receptors with Ki = 3.9 and 1.7 nM, respectively. 相似文献
10.
Peschke B Bak S Hohlweg R Pettersson I Refsgaard HH Viuff D Rimvall K 《Bioorganic & medicinal chemistry》2004,12(10):2603-2616
New imidazole-free H3 antagonists have been found in a series of cinnamic amides of (S)-(aminomethyl)pyrrolidines. The influence of the substituent on the aromatic moiety on the potency and the inhibition of three cytochrome P450 subtypes are also described. 相似文献
11.
Shah C McAtee L Breitenbucher JG Rudolph D Li X Lovenberg TW Mazur C Wilson SJ Carruthers NI 《Bioorganic & medicinal chemistry letters》2002,12(22):3309-3312
High throughput screening, using the recombinant human H(3) receptor, was used to identify novel histamine H(3) receptor antagonists. Evaluation of the lead compounds ultimately afforded potent, selective, orally bioavailable compounds (e.g., 38) with favorable blood-brain barrier penetration. 相似文献
12.
Berlin M Ting PC Vaccaro WD Aslanian R McCormick KD Lee JF Albanese MM Mutahi MW Piwinski JJ Shih NY Duguma L Solomon DM Zhou W Sher R Favreau L Bryant M Korfmacher WA Nardo C West RE Anthes JC Williams SM Wu RL Susan She H Rivelli MA Corboz MR Hey JA 《Bioorganic & medicinal chemistry letters》2006,16(4):989-994
A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established. 相似文献
13.
Olga Ciupak Mateusz Dako Karol Biernacki Janusz Rachon Maciej Masyk Konrad Kubiski Aleksandra Martyna Sebastian Demkowicz 《Journal of enzyme inhibition and medicinal chemistry》2021,36(1):238
In the present work, we report a new class of potent steroid sulphatase (STS) inhibitors based on 6-(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives. Within the set of new STS inhibitors, 6-(1-(1,2,3-trifluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate 3L demonstrated the highest activity in the enzymatic assay inhibiting the STS activity to 7.98% at 0.5 µM concentration. Furthermore, to verify whether the obtained STS inhibitors are able to pass through the cellular membrane effectively, cell line experiments have been carried out. We found that the lowest STS activities were measured in the presence of compound 3L (remaining STS activity of 5.22%, 27.48% and 99.0% at 100, 10 and 1 nM concentrations, respectively). The measured STS activities for Irosustat (used as a reference) were 5.72%, 12.93% and 16.83% in the same concentration range. Moreover, a determined IC50 value of 15.97 nM for 3L showed that this compound is a very promising candidate for further preclinical investigations. 相似文献
14.
Fujio M Kuroita T Sakai Y Nakagawa H Matsumoto Y 《Bioorganic & medicinal chemistry letters》2000,10(21):2457-2461
A series of 1-adamantanecarboxamides was synthesized and examined for their potency as a selective 5-HT2 receptor antagonist. We found (S)-N-[1-[2-(4-fluorophenyl)ethyl]pyrrolidin-3-yl]-1-adamantane carboxamide hydrochloride hydrate (10-(S), Y-39241) to have a high affinity and selectivity for 5-HT2 receptors, and this potent anti-platelet effect of Y-39241 was confirmed both in vitro and in vivo. 相似文献
15.
Letavic MA Keith JM Ly KS Bonaventure P Feinstein MA Lord B Miller KL Motley ST Nepomuceno D Sutton SW Carruthers NI 《Bioorganic & medicinal chemistry letters》2008,18(21):5796-5799
The synthesis and biological activity of a new series of 2-aryloxymethylmorpholine histamine H(3) antagonists is described. The new compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain. 相似文献
16.
Shinya Harusawa Koichi Sawada Takuji Magata Hiroki Yoneyama Lisa Araki Yoshihide Usami Kouta Hatano Kouichi Yamamoto Daisuke Yamamoto Atsushi Yamatodani 《Bioorganic & medicinal chemistry letters》2013,23(23):6415-6420
S-Alkyl-N-alkylisothiourea compounds containing various cyclic amines were synthesized in the search for novel nonimidazole histamine H3 receptor (H3R) antagonists. Among them, four N-alkyl S-[3-(piperidin-1-yl)propyl]isothioureas 18, 19, 22, and 23 were found to exhibit potent and selective H3R antagonistic activities against in vitro human H3R, but were inactive against in vitro human H4R. Furthermore, three alkyl homologs 18–20 showed inactivity for histamine release in in vivo rat brain microdialysis, suggesting differences in antagonist affinities between species. In addition, in silico docking studies of N-[4-(4-chlorophenyl)butyl]-S-[3-piperidin-1-yl)propyl]isothiourea 19 and a shorter homolog 17 with human/rat H3Rs revealed that structural differences between the antagonist-docking cavities of rat and human H3Rs were likely caused by the Ala122/Val122 mutation. 相似文献
17.
Napier SE Letourneau JJ Ansari N Auld DS Baker J Best S Campbell-Wan L Chan R Craighead M Desai H Ho KK MacSweeney C Milne R Richard Morphy J Neagu I Ohlmeyer MH Pick J Presland J Riviello C Zanetakos HA Zhao J Webb ML 《Bioorganic & medicinal chemistry letters》2011,21(12):3813-3817
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V1b antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V1b receptor and good selectivity with respect to related receptors V1a, V2 and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction. 相似文献
18.
The antipsychotic profile of 5-[2-[4-(6-fluoro-1H-indole-3-yl)piperidin-1-yl]ethyl]-4-(4-fluorophenyl)thiazole-2-carboxylic acid amide (NRA0562) was investigated using the conditioned avoidance test in rats. NRA0562 is a putative "atypical" antipsychotic agent with moderate to high affinities for dopamine D(1), D(2), D(4), 5-hydroxytryptamine(2A) receptors and alpha(1) adrenoceptor. NRA0562 (1 and 3 mg/kg, p.o.) dose-dependently and significantly impaired the conditioned avoidance response. Likewise other atypical antipsychotics such as risperidone (1 and 3 mg/kg, p.o.) and clozapine (100 mg/kg, p.o.) dose-dependently and significantly impaired the conditioned avoidance response in rats. In addition, typical antipsychotics, haloperidol (1 and 3 mg/kg, p.o.) potently impaired the conditioned avoidance response.These results suggest that antipsychotic profile of NRA0562 is consistent with profiles of clozapine or risperidone and may be considered an atypical antipsychotic agent. 相似文献
19.
Matulenko MA Surber B Fan L Kolasa T Nakane M Terranova MA Uchic ME Miller LN Chang R Donnelly-Roberts DL Namovic MT Moreland RB Brioni JD Stewart AO 《Bioorganic & medicinal chemistry letters》2004,14(20):5095-5098
The first selective dopamine D4 agonist radioligand is described. The synthesis of these piperazine radioligands relied on the transformation of brominated precursors 4a and 4b with tritium gas in the presence of a sensitive cyano functional group. The specific activity of these two radioligands was measured and [3H]6b found to be suitable for use in D4 saturation and competition binding studies. The synthesis, biological, and radioactivity of this new agonist radioligand as well as preliminary SAR will be discussed. 相似文献
20.
Nitta A Fujii H Sakami S Nishimura Y Ohyama T Satoh M Nakaki J Satoh S Inada C Kozono H Kumagai H Shimamura M Fukazawa T Kawai H 《Bioorganic & medicinal chemistry letters》2008,18(20):5435-5438
Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides and 3-amino-N-(4-aryltetrahydropyran-4-yl)butanamides were synthesized and evaluated as dipeptidyl peptidase IV (DPP-IV) inhibitors. Derivatives incorporating the 6-substituted benzothiazole group showed highly potent DPP-IV inhibitory activity. Oral administration of (3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide (12u) reduced blood glucose excursion in an oral glucose tolerance test. 相似文献