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1.
Target selective drugs, such as dopamine receptor (DR) subtype selective ligands, are developed for enhanced therapeutics and reduced side effects. In silico methods have been explored for searching DR selective ligands, but encountered difficulties associated with high subtype similarity and ligand structural diversity. Machine learning methods have shown promising potential in searching target selective compounds. Their target selective capability can be further enhanced. In this work, we introduced a new two-step support vector machines target-binding and selectivity screening method for searching DR subtype-selective ligands, which was tested together with three previously-used machine learning methods for searching D1, D2, D3 and D4 selective ligands. It correctly identified 50.6%-88.0% of the 21-408 subtype selective and 71.7%-81.0% of the 39-147 multi-subtype ligands. Its subtype selective ligand identification rates are significantly better than, and its multi-subtype ligand identification rates are comparable to the best rates of the previously used methods. Our method produced low false-hit rates in screening 13.56 M PubChem, 168,016 MDDR and 657,736 ChEMBLdb compounds. Molecular features important for subtype selectivity were extracted by using the recursive feature elimination feature selection method. These features are consistent with literature-reported features. Our method showed similar performance in searching estrogen receptor subtype selective ligands. Our study demonstrated the usefulness of the two-step target binding and selectivity screening method in searching subtype selective ligands from large compound libraries. 相似文献
2.
Matasi JJ Caldwell JP Hao J Neustadt B Arik L Foster CJ Lachowicz J Tulshian DB 《Bioorganic & medicinal chemistry letters》2005,15(5):1333-1336
In high throughput screening of our file compounds, a novel structure 1 was identified as a potent A(2A) receptor antagonist with no selectivity over the A1 adenosine receptor. The structure-activity relationship investigation using 1 as a template lead to identification of a novel class of compounds as potent and selective antagonists of A(2A) adenosine receptor. Compound 26 was identified to be the most potent A(2A) receptor antagonist (Ki = 0.8 nM) with 100-fold selectivity over the A1 adenosine receptor. 相似文献
3.
Quinazolines as adenosine receptor antagonists: SAR and selectivity for A2B receptors 总被引:1,自引:0,他引:1
Webb TR Lvovskiy D Kim SA Ji Xd Melman N Linden J Jacobson KA 《Bioorganic & medicinal chemistry》2003,11(1):77-85
We have recently reported the discovery of numerous new compounds that are selective inhibitors of all of the subtypes of the adenosine receptor family via a pharmacophore database searching and screening strategy. During the course of this work we made the unexpected discovery of a potent A(2B) receptor antagonist, 4-methyl-7-methoxyquinazolyl-2-(2'-amino-4'-imidazolinone) (38, CMB 6446), which showed selectivity for this receptor and functioned as an antagonist, with a binding K(i) value of 112 nM. We explored the effects of both substituent- and ring-structural variations on the receptor affinity in this series of derivatives, which were found to be mostly non-selective adenosine receptor ligands with K(i) values in the micromolar range. Since no enhancement of A(2B) receptor affinity of 38 was achieved, the previously reported pharmacophore-based searching strategy yielded the most potent and selective structurally-related hit in the database originally searched. 相似文献
4.
Lovell PJ Blaney FE Goodacre CJ Scott CM Smith PW Starr KR Thewlis KM Vong AK Ward SE Watson JM 《Bioorganic & medicinal chemistry letters》2007,17(4):1033-1036
Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat. 相似文献
5.
Wilson KJ van Niel MB Cooper L Bloomfield D O'Connor D Fish LR MacLeod AM 《Bioorganic & medicinal chemistry letters》2007,17(9):2643-2648
This report describes the effect of replacing the central basic amine present in many known 5-HT(2A) ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT(2A) receptor binding affinity and selectivity over the 5-HT(2C) subtype. Optimization of one isomer led to the identification of 25, a compound with sub-nanomolar 5-HT(2A) affinity and selectivity over 5-HT(2C) of greater than 4600-fold. 相似文献
6.
MS Malamas H Stange R Schindler HJ Lankau C Grunwald B Langen U Egerland T Hage Y Ni J Erdei KY Fan K Parris KL Marquis S Grauer J Brennan R Navarra R Graf BL Harrison A Robichaud T Kronbach MN Pangalos NJ Brandon N Hoefgen 《Bioorganic & medicinal chemistry letters》2012,22(18):5876-5884
The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2mg/kg). 相似文献
7.
Humphries PS Bailey S Almaden JV Barnum SJ Carlson TJ Christie LC Do QQ Fraser JD Hess M Kellum J Kim YH McClellan GA Ogilvie KM Simmons BH Skalitzky D Sun S Wilhite D Zehnder LR 《Bioorganic & medicinal chemistry letters》2006,16(23):6120-6123
A series of novel pyridine-3-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compounds (S)-14 and (S)-19 were selected for further profiling. 相似文献
8.
Cacciari B Bolcato C Spalluto G Klotz KN Bacilieri M Deflorian F Moro S 《Purinergic signalling》2007,3(3):183-193
In the last 5 years, many efforts have been conducted searching potent and selective human A(3) adenosine antagonists. In this field several different classes of compounds, possessing very good affinity (nM range) and with a broad range of selectivity, have been proposed. Recently, our group synthesized a new series of pyrazolo-triazolo-pyrimidines bearing different substitutions at the N(5) and N(8) positions, which have been described as highly potent and selective human A(3) adenosine receptor antagonists. The present review summarizes available data and provides an overview of the structure-activity relationships found for this class of human A(3) adenosine receptor antagonists. 相似文献
9.
Humphries PS Almaden JV Barnum SJ Carlson TJ Do QQ Fraser JD Hess M Kim YH Ogilvie KM Sun S 《Bioorganic & medicinal chemistry letters》2006,16(23):6116-6119
A series of novel pyridine-2-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compound (S)-13 was selected for further profiling. 相似文献
10.
Firooznia F Cheung AW Brinkman J Grimsby J Gubler ML Hamid R Marcopulos N Ramsey G Tan J Wen Y Sarabu R 《Bioorganic & medicinal chemistry letters》2011,21(7):1933-1936
The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A2B antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A2A and A1 receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A2A and A1 receptors. 相似文献
11.
G Galley H Stalder A Goergler MC Hoener RD Norcross 《Bioorganic & medicinal chemistry letters》2012,22(16):5244-5248
A series of imidazole compounds has been identified which affords potent and selective partial and full agonists of the TAAR1 receptor. Starting from 2-benzyl-imidazoline screening hits, a series of structurally related 2-benzyl- and 4-benzyl-imidazoles was investigated first, but it proved highly challenging to obtain compounds having sufficient selectivity against the adrenergic alpha 2 receptor. This issue could be successfully addressed by modification of the linker region and SAR exploration led to the discovery of highly selective isopropyl-substituted 4-aminomethyl-imidazole compounds. The work culminated in the identification of the selective TAAR1 partial agonist RO5073012 (4-chlorophenyl)-(1H-imidazol-4-ylmethyl)-isopropyl-amine, 24), which has a good pharmacokinetic profile after oral administration in rodents. RO5073012 has been found to be active in a behavioural rat model which is considered indicative for schizophrenia. 相似文献
12.
Drabczyńska A Müller CE Karolak-Wojciechowska J Schumacher B Schiedel A Yuzlenko O Kieć-Kononowicz K 《Bioorganic & medicinal chemistry》2007,15(14):5003-5017
Synthesis and physicochemical properties of N-benzyl pyrimido[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-chloropropylo-8-bromo-1,3-dimethyl- or 1,3-dipropyl xanthine derivatives with corresponding (un)substituted benzylamines. Dipropyl derivatives were obtained under microwave irradiation conditions either. The obtained compounds (1-20) were evaluated for their affinity to adenosine A1 and A2A receptors, selected compounds were additionally investigated for affinity to the A3 receptor subtype. The results of the radioligand binding assays to A1 and A2A adenosine receptors showed that most of the 1,3-dimethyl-9-benzylpyrimidopurinediones exhibited selective affinity to A2A receptors at micromolar or submicromolar concentrations (for example, derivative 9 with o-methoxy substituent displayed a Ki value of 0.699 microM at rat A2A receptor with more than 36-fold selectivity). Contrary to previously described arylpyrimido[2,1-f]purinediones dipropyl derivatives (compounds 15-20) showed affinity to both kinds of receptors increased, however A1 affinity increased to a larger extent, with the result that A2A selectivity was abolished. The best adenosine A1 receptor ligand was m-chlorobenzyl derivative 18 (Ki=0.089 microM and 5-fold A1 selectivity). Structure-activity relationships were discussed with the analysis of lipophilic and spatial properties of the investigated compounds. Pharmacophore model of adenosine A1 receptor antagonist was adopted for this purpose. 相似文献
13.
14.
Discovery of N-(2-aryl-cyclohexyl) substituted spiropiperidines as a novel class of GlyT1 inhibitors
Pinard E Ceccarelli SM Stalder H Alberati D 《Bioorganic & medicinal chemistry letters》2006,16(2):349-353
Screening of the Roche compound library led to the identification of cis-N-(2-phenyl-cyclohexyl)-spiropiperidine 1 as structurally novel GlyT1 inhibitor. The SAR, which was developed in this series, resulted in the discovery of highly potent compounds displaying excellent selectivity against the GlyT2 isoform. 相似文献
15.
Gilbert AM Stack GP Nilakantan R Kodah J Tran M Scerni R Shi X Smith DL Andree TH 《Bioorganic & medicinal chemistry letters》2004,14(2):515-518
2,3-Dihydro-1,4-benzodioxanes with aryl 8-aza-bicyclo[3.2.1]oct-3-ene attachments 2 produce compounds with potent 5-HT-T affinity, and weak 5-HT(1A) affinity and alpha(1) affinity. This compares with 2,3-dihydro-1,4-benzodioxanes containing 8-aza-bicyclo[3.2.1] octan-3-ol attachments 4 which possess potent 5-HT(1A) affinity, moderate to good selectivity over alpha(1) and little 5-HT-T affinity. A 3-benzothiophene analogue of 4 (30) was synthesized which possesses potent 5-HT(1A) affinity and especially good selectivity over both alpha(1) and 5-HT-T. 相似文献
16.
Yoshizumi T Takahashi H Ohtake N Jona H Sato Y Kishino H Sakamoto T Ozaki S Takahashi H Shibata Y Ishii Y Saito M Okada M Hayama T Nishikibe M 《Bioorganic & medicinal chemistry》2004,12(9):2139-2150
The synthesis and structure-activity relationships of a series of 5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids are described. Our efforts have been focused on modification of the aryl ring at the 5-position and the alkyl substituent at the 2-position of the bottom 4-methoxyphenyl ring in an effort to develop orally available ET(A) selective antagonists with safer profiles in terms of the P-450 enzyme inhibitory activity. Incorporation of a hydroxymethyl group as an alkyl substituent in methylenedioxyphenyl and 6-dihydrobenzofuran derivatives led to the identification of orally bioavailable ET(A) selective antagonists 1f and 7f. These compounds also showed not only excellent binding affinity (IC(50) < 0.10nM, more than 800-fold selectivity for the ET(A) receptor over the ET(B) receptor) but also sufficient oral bioavailability, 48% and 56%, respectively, in rats. Furthermore, these compounds did not exhibit either competitive or mechanism-based inhibition of human cytochrome P450 enzymes. 相似文献
17.
Fish LR Gilligan MT Humphries AC Ivarsson M Ladduwahetty T Merchant KJ O'Connor D Patel S Philipps E Vargas HM Hutson PH MacLeod AM 《Bioorganic & medicinal chemistry letters》2005,15(16):3665-3669
Incorporation of fluorine at the 4-position of an existing series of sulfonyl piperidine 5-HT2A antagonists gave compounds with increased selectivity over the IKr potassium channel. This work led to the identification of 3b, a compound that gave no increase in QTc in the anesthetized dog up to plasma levels as high as 148 microM. Furthermore, 3b has been shown to increase slow-wave sleep bout duration and to decrease the number of awakenings in rats, indicating the potential utility of 5-HT2A antagonists in the treatment of insomnia. 相似文献
18.
Eduard Badarau Franck Suzenet Andrzej J. Bojarski Adriana-Luminiţa Fînaru Gérald Guillaumet 《Bioorganic & medicinal chemistry letters》2009,19(6):1600-1603
A new group of serotoninergic 5-HT1A or 5-HT7 receptor ligands was identified. These compounds were designed and synthesized on a benzimidazolone scaffold and they enrich the well-known arylpiperazine class of 5-HT ligands. Diverse pharmacomodulations induced a shift in the affinity and selectivity profile with final identification of new potent hits. 相似文献
19.
Topai A Breccia P Minissi F Padova A Marini S Cerbara I 《Bioorganic & medicinal chemistry》2012,20(7):2323-2337
Among matrix metalloproteinases (MMPs), gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B) play a key role in a number of physiological processes such as tissue repair and fibrosis. Many evidences point out their involvement in a series of pathological events, such as arthritis, multiple sclerosis, cardiovascular diseases, inflammatory processes and tumor progression by degradation of the extracellular matrix. To date, the identification of non-specific MMP inhibitors has made difficult the selective targeting of gelatinases. In this work we report the identification, design and synthesis of new gelatinase inhibitors with appropriate drug-like properties and good profile in terms of affinity and selectivity. By a detailed in silico protocol and innovative and versatile solid phase approaches, a series of 4-thiazolydinyl-N-hydroxycarboxyamide derivatives were identified. In particular, compounds 9a and 10a showed a potent inhibitory activity against gelatinase B and good selectivity over the other MMP considered in this study. The identified compounds could represent novel potential candidates as therapeutic agents. 相似文献
20.
L L Chang K L Sidler M A Cascieri S de Laszlo G Koch B Li M MacCoss N Mantlo S O'Keefe M Pang A Rolando W K Hagmann 《Bioorganic & medicinal chemistry letters》2001,11(18):2549-2553
A modestly active, nonselective triarylimidazole lead was optimized for binding affinity with the human glucagon receptor. This led to the identification of a 2- and/or 4-alkyl or alkyloxy substituent on the imidazole C4-aryl group as a structural determinant for significant enhancement in binding with the glucagon receptor (e.g., 41, IC(50)=0.053 microM) and selectivity (>1000x) over p38MAP kinase in this class of compounds. 相似文献