共查询到20条相似文献,搜索用时 15 毫秒
1.
Kopka IE Lin LS Mumford RA Lanza T Magriotis PA Young D DeLaszlo SE MacCoss M Mills SG Van Riper G McCauley E Lyons K Vincent S Egger LA Kidambi U Stearns R Colletti A Teffera Y Tong S Owens K Levorse D Schmidt JA Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(17):2415-2418
A series of substituted N-(3,5-dichlorobenzenesulfonyl)-(L)-prolyl- and (L)-azetidyl-beta-biaryl beta-alanine derivatives was prepared as selective and potent VLA-4 antagonists. The 2,6-dioxygenated biaryl substitution pattern is important for optimizing potency. Oral bioavailability was variable and may be a result of binding to circulating plasma proteins. 相似文献
2.
Kamenecka TM Lanza T de Laszlo SE Li B McCauley ED Van Riper G Egger LA Kidambi U Mumford RA Tong S MacCoss M Schmidt JA Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(16):2205-2208
The design, synthesis, and biological evaluation of N-arylprolyl-dipeptide derivatives as small molecule VLA-4 antagonists is described. Potency against VLA-4 and alpha(4)beta(7) and rat pharmacokinetic evaluation revealed some advantages over the related N-(arylsulfonyl)-prolyl-dipeptide analogues. 相似文献
3.
Thomas S. Reger Jasmine Zunic Nicholas Stock Bowei Wang Nicholas D. Smith Benito Munoz Mitchell D. Green Michael F. Gardner Joyce P. James Weichao Chen Kenneth Alves Qian Si Kelly M. Treonze Russell B. Lingham Richard A. Mumford 《Bioorganic & medicinal chemistry letters》2010,20(3):1173-1176
A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics. 相似文献
4.
Lassoie MA Broeders F Collart P Defrère L de Laveleye-Defais F Demaude T Gassama A Guillaumet G Hayez JC Kiss L Knerr L Nicolas JM Norsikian S Quéré L Routier S Verbois V Provins L 《Bioorganic & medicinal chemistry letters》2007,17(1):142-146
A new series of 2,6-quinolinyl derivatives was prepared leading to potent low nanomolar VLA-4/VCAM-1 antagonists. 相似文献
5.
Lin LS Kopka IE Mumford RA Magriotis PA Lanza T Durette PL Kamenecka T Young DN de Laszlo SE McCauley E Riper GV Kidambi U Egger LA Tong X Lyons K Vincent S Stearns R Colletti A Teffera Y Fenyk-Melody J Schmidt JA MacCoss M Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(4):611-614
Acylated beta-amino acids are described as potent, specific and orally bioavailable antagonists of VLA-4. The initial lead was identified from a combinatorial library. Subsequent optimization using a traditional medicinal chemistry approach led to significant improvement in potency (up to 8-fold) while maintaining good pharmacokinetic properties. 相似文献
6.
Li B de Laszlo SE Kamenecka TM Kopka IE Durette PL Lanza T MacCoss M Tong S Mumford RA McCauley ED Van Riper G Schmidt JA Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(16):2141-2144
A series of potent N-(aralkyl-, arylcycloalkyl-, and heteroaryl-acyl)-4-biphenylalanine VLA-4 antagonists was prepared by rapid analogue methods using solid-phase chemistry. Further optimization led to several highly potent compounds (IC(50) <1 nM). Evaluation of rat pharmacokinetic revealed generally high clearance. 相似文献
7.
Chen L Tilley JW Huang TN Miklowski D Trilles R Guthrie RW Luk K Hanglow A Rowan K Schwinge V Wolitzky B 《Bioorganic & medicinal chemistry letters》2000,10(8):725-727
We have identified a series of low molecular weight (Mr < 500) N-acylphenylalanines that are effective inhibitors of the VCAM-VLA-4 interaction. Investigation of the SAR of the N-acyl moiety led to the identification of N-benzylpyroglutamyl derivatives as being particularly potent. 相似文献
8.
Hagmann WK Durette PL Lanza T Kevin NJ de Laszlo SE Kopka IE Young D Magriotis PA Li B Lin LS Yang G Kamenecka T Chang LL Wilson J MacCoss M Mills SG Van Riper G McCauley E Egger LA Kidambi U Lyons K Vincent S Stearns R Colletti A Teffera J Tong S Fenyk-Melody J Owens K Levorse D Kim P Schmidt JA Mumford RA 《Bioorganic & medicinal chemistry letters》2001,11(20):2709-2713
Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented. 相似文献
9.
10.
Witherington J Blaney EL Bordas V Elliott RL Gaiba A Garton N Green PM Naylor A Smith DG Spalding DJ Takle AK Ward RW 《Bioorganic & medicinal chemistry letters》2006,16(21):5538-5541
A series of pyridone-N-benzyl-propanoic acids have been optimised to afford potent orally bioavailable VLA-4 antagonists. 相似文献
11.
Yang GX Chang LL Truong Q Doherty GA Magriotis PA de Laszlo SE Li B MacCoss M Kidambi U Egger LA McCauley E Van Riper G Mumford RA Schmidt JA Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(11):1497-1500
Given the proposed involvement of VLA-4 in inflammatory processes, a program to identify orally active VLA-4 antagonists was initiated. Herein, we report the discovery of a N-tetrahydrofuroyl-(L)-phenylalanine derivative (17) and related analogues as potent VLA-4 antagonists with good oral bioavailability. 相似文献
12.
Doherty GA Yang GX Borges E Chang LL MacCoss M Tong S Kidambi U Egger LA McCauley E Van Riper G Mumford RA Schmidt JA Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(11):1501-1505
A series of substituted tetrahydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the alpha carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus alpha(4)beta(7) while amide substitution increased the potency of the series without increasing the specificity. Substitution of the beta carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus alpha(4)beta(7) but with a significant loss in binding affinity for VLA-4. 相似文献
13.
Ying-zi Xu Andrei W. Konradi Frederique Bard Michael Dappen Lilibeth Dofiles Mark Dreyer Ian Gallager Caroline Garrido Mike Krimm Zhenmei Liao Elizabeth Messersmith Linda Mutter Michael A. Pleiss Bhushan Samant Christopher M. Semko Jennifer Smith Frank Stappenbeck Brian Stupi Ted Yednock 《Bioorganic & medicinal chemistry letters》2013,23(10):3070-3074
A series of (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid is discovered as orally available VLA-4 antagonists. Representative compounds 11b and 11p showed efficacy in multiple in vivo animal models. The in vitro selectivity of 11p is also described. 相似文献
14.
Phillips DJ Davenport RJ Demaude TA Galleway FP Jones MW Knerr L Perry BG Ratcliffe AJ 《Bioorganic & medicinal chemistry letters》2008,18(14):4146-4149
We describe a novel series of imidazopyridine substituted phenylalanines which are potent VLA-4 antagonists. A wide variety of substituents are tolerated as replacements for the pendant 3-pyridyl ring. A clear structure–activity relationship was identified around the substitution of the 3-amino-cyclobut-2-enone portion of the molecule. 相似文献
15.
Kopka IE Young DN Lin LS Mumford RA Magriotis PA MacCoss M Mills SG Van Riper G McCauley E Egger LE Kidambi U Schmidt JA Lyons K Stearns R Vincent S Colletti A Wang Z Tong S Wang J Zheng S Owens K Levorse D Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(4):637-640
A series of substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl- and alpha-methyl-L-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC50 approximately 1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series. 相似文献
16.
Li Chen Jefferson Tilley Richard V Trilles Weiya Yun David Fry Charles Cook Karen Rowan Virginia Schwinge Robert Campbell 《Bioorganic & medicinal chemistry letters》2002,12(2):137-140
A series of N-benzylpyroglutamyl-L-phenylalanine derivatives bearing carbamoyl substituents in the 3- or 4-positions was prepared and assayed for inhibition of the interaction between VCAM and VLA-4. Potent inhibition was observed in a number of analogues with substitution in the 4-position favored over the 3-position. A crystal structure of the key intermediate 25 indicates that it accesses a low energy conformation which closely matches key pharmacophores of a structurally characterized cyclic peptide. 相似文献
17.
Porter JR Archibald SC Brown JA Childs K Critchley D Head JC Parton TA Robinson MK Shock A Taylor RJ Warrellow GJ 《Bioorganic & medicinal chemistry letters》2003,13(5):805-808
We describe a series of dehydrophenylalanine derivatives where the Z isomers are potent VLA-4 antagonists but are subject to rapid biliary clearance and the E isomers have poor activity but have a slower rate of clearance. These configurationally constrained molecules have led to the design of a novel class of benzodiazepine VLA-4 antagonists. 相似文献
18.
Porter JR Archibald SC Childs K Critchley D Head JC Linsley JM Parton TA Robinson MK Shock A Taylor RJ Warrellow GJ Alexander RP Langham B 《Bioorganic & medicinal chemistry letters》2002,12(7):1051-1054
SAR studies aimed at improving the rate of clearance by the incorporation of a 3,4-diamino-3-cyclobutene-1,2-dione group as an amino acid isostere in a series of VLA-4 integrin antagonists are described. 相似文献
19.
Sidduri A Tilley JW Hull K Lou JP Kaplan G Sheffron A Chen L Campbell R Guthrie R Huang TN Huby N Rowan K Schwinge V Renzetti LM 《Bioorganic & medicinal chemistry letters》2002,12(17):2475-2478
A systematic structure-activity relationship investigation of the lead compound 1 resulted the identification of several N-[(substituted alkyl)cycloalkanoyl]-4-[((2,6-dichlorophenyl)carbonyl)amino]-L-phenylalanine derivatives as potent VCAM/VLA-4 antagonists. The data are consistent with a model of these compounds in which these alkanoylphenylalanines reside in a compact gauche (-) bioactive conformation. 相似文献
20.
Doherty GA Kamenecka T McCauley E Van Riper G Mumford RA Tong S Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(5):729-731
A series of N-arylated phenylalanine derivatives has been synthesized and has been shown to be potent inhibitors of the integrin VLA-4. N-phenyl and N-heteroaryl derivatives with hydrogen bond acceptors in the meta position demonstrated low nanomolar activity against VLA-4. 相似文献