共查询到20条相似文献,搜索用时 46 毫秒
1.
Sturino CF Lachance N Boyd M Berthelette C Labelle M Li L Roy B Scheigetz J Tsou N Brideau C Cauchon E Carriere MC Denis D Greig G Kargman S Lamontagne S Mathieu MC Sawyer N Slipetz D O'Neill G Wang Z Zamboni R Metters KM Young RN 《Bioorganic & medicinal chemistry letters》2006,16(11):3043-3048
A novel indole series of PGD2 receptor (DP receptor) antagonists is presented. Optimization of this series led to the identification of potent and selective DP receptor antagonists. In particular, antagonists 35 and 36 were identified with Ki values of 2.6 and 1.8 nM, respectively. These two antagonists are also potent in a DP functional assay where they inhibit the PGD2 induced cAMP production in platelet rich plasma with IC50 values of 7.9 and 8.6 nM, respectively. The structure-activity relationships of this indole series of DP receptor antagonists will also be discussed. 相似文献
2.
Hassen Ratni Theresa M. Ballard Caterina Bissantz Torsten Hoffmann Philippe Jablonski Frederic Knoflach Henner Knust Parichehr Malherbe Matthias Nettekoven Angelique Patiny-Adam Claus Riemer Monique Schmitt Will Spooren 《Bioorganic & medicinal chemistry letters》2010,20(22):6735-6738
The rational design of a novel series of pyrrolidine derivatives as neurokinin-3 receptor antagonists is reported starting from a selective neurokinin-1 receptor antagonist. Typical representatives in this series showed in vivo efficacy after oral administration in a NK3 mediated functional assay. This series of NK3 antagonists shows promise to deliver a novel antipsychotic. 相似文献
3.
DeVita RJ Parikh M Jiang J Fair JA Young JR Walsh TF Goulet MT Lo JL Ren N Yudkovitz JB Cui J Yang YT Cheng K Rohrer SP Wyvratt MJ 《Bioorganic & medicinal chemistry letters》2004,14(22):5599-5603
A series of neutral, nonbasic quinolone GnRH antagonists were prepared via Mitsunobu alkylation of protected and unprotected 4-hydroxy quinolone intermediates. The synthetic route was improved by utilization of unique reactivity and convergency afforded by the use of mono and bis-trimethylsilylethyl protected quinolones. Potent neutral GnRH antagonists were identified, including ether and lactam derivatives, that show similar in vitro binding affinity and functional activity as compared to the earlier basic 4-aminoalkyl quinolone series of nonpeptide GnRH antagonists. 相似文献
4.
Jiwen Liu Zice Fu Yingcai Wang Mike Schmitt Alan Huang Derek Marshall George Tonn Lisa Seitz Tim Sullivan H. Lucy Tang Tassie Collins Julio Medina 《Bioorganic & medicinal chemistry letters》2009,19(22):6419-6423
A series of phenylacetic acid derivatives was discovered as CRTH2 antagonists. Modification of the series led to compounds that are also antagonists of DP. Since activation of CRTH2 and DP are believed to play key roles in mediating responses of asthma and other immune diseases, this series was optimized to increase the dual antagonistic activities and improve pharmacokinetic properties. These efforts led to selection of AMG 009 as a clinical candidate. 相似文献
5.
Brashear KM Hunt CA Kucer BT Duggan ME Hartman GD Rodan GA Rodan SB Leu CT Prueksaritanont T Fernandez-Metzler C Barrish A Homnick CF Hutchinson JH Coleman PJ 《Bioorganic & medicinal chemistry letters》2002,12(23):3483-3486
A series of novel, highly potent alpha(v)beta(3) receptor antagonists with favorable pharmacokinetic profiles has been identified. In this series of antagonists, 2-aryl beta-amino acids function as potent aspartic acid replacements. 相似文献
6.
Coleman PJ Askew BC Hutchinson JH Whitman DB Perkins JJ Hartman GD Rodan GA Leu CT Prueksaritanont T Fernandez-Metzler C Merkle KM Lynch R Lynch JJ Rodan SB Duggan ME 《Bioorganic & medicinal chemistry letters》2002,12(17):2463-2465
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared where deletion of an amide bond from an earlier series of linear RGD-mimetics provides a novel series of chain-shortened alpha(v)beta(3) antagonists with significantly improved oral pharmacokinetics. These chain-shortened alpha(v)beta(3) antagonists represent structurally novel integrin inhibitors. 相似文献
7.
Johnson SG Gunnet JW Moore JB Miller W Wines P Rivero RA Combs D Demarest KT 《Bioorganic & medicinal chemistry letters》2006,16(13):3362-3366
A series of 1,3-disubstituted cyclohexylmethyl urea and amide derivatives were synthesized as motilin receptor antagonists. Starting from known motilin antagonists, 1a and 1b, the cyclopentene scaffold was replaced and the four recognition elements optimized to arrive at a potent novel series. 相似文献
8.
Judd AS Souers AJ Wodka D Zhao G Mulhern MM Iyengar RR Gao J Lynch JK Freeman JC Falls HD Brodjian S Dayton BD Reilly RM Gintant G Limberis JT Mikhail A Leitza ST Houseman KA Diaz G Bush EN Shapiro R Knourek-Segel V Hernandez LE Marsh KC Sham HL Collins CA Kym PR 《Bioorganic & medicinal chemistry letters》2007,17(8):2365-2371
A series of potent 2-carboxychromone-based melanin-concentrating hormone receptor 1 (MCHr1) antagonists were synthesized and evaluated for hERG (human Ether-a-go-go Related Gene) channel affinity and functional blockade. Basic dialkylamine-terminated analogs were found to weakly bind the hERG channel and provided marked improvement in a functional patch-clamp assay versus previously reported antagonists of the series. 相似文献
9.
McCleland BW Davis RS Palovich MR Widdowson KL Werner ML Burman M Foley JJ Schmidt DB Sarau HM Rogers M Salyers KL Gorycki PD Roethke TJ Stelman GJ Azzarano LM Ward KW Busch-Petersen J 《Bioorganic & medicinal chemistry letters》2007,17(6):1713-1717
N,N'-diarylsquaramides were prepared and evaluated as antagonists of CXCR2. The compounds were found to be potent and selective antagonists of CXCR2. Significant differences in SAR was observed relative to the previously described N,N'-diarylurea series. As was the case in the N,N'-diarylurea series, placing sulfonamide substituent adjacent to the acidic phenol significantly reduced the clearance in rat pharmacokinetic studies. 相似文献
10.
Barbay JK Gong Y Buntinx M Li J Claes C Hornby PJ Van Lommen G Van Wauwe J He W 《Bioorganic & medicinal chemistry letters》2008,18(8):2544-2548
A novel series of substituted 2-aryl-5-amino-5,6,7,8-tetrahydroquinoline C5a receptor antagonists is reported. Synthetic routes were developed that allow the substituents on the tetrahydroquinoline core to be efficiently varied, facilitating determination of structure-activity relationships. Members of the series display high binding affinity for the C5a receptor and are potent functional antagonists. 相似文献
11.
Huang CQ Grigoriadis DE Liu Z McCarthy JR Ramphal J Webb T Whitten JP Xie MY Chen C 《Bioorganic & medicinal chemistry letters》2004,14(9):2083-2086
A series of 2-dialkylamino-4-phenylpyrimidines (7) was designed and synthesized as CRF(1) antagonists. SAR studies of this series resulted in the discovery of potent and selective antagonists 7b and 7n bearing a 4-(2,4,6-trisubstituted-phenyl) ring and a bulky 2-(N-bis(cyclopropane)methyl-N-propyl)amino group. 相似文献
12.
Michael J. Sofia William T. Jackson Davis L. SaussyJr. Steven A. Silbaugh Larry L. Froelich Sandra L. Cockerham Peter W. Stengel 《Bioorganic & medicinal chemistry letters》1992,2(12):1669-1674
A series of
-alkoxyphenols containing a tetrazole acid sidechain have been prepared as antagonists of leukotriene B4 receptors. These compounds were tested as receptor antagonists of human neutrophil and guinea pig lung membrane leukotriene B4 receptors. Compounds in this series were found to be up to 18-fold more potent than LY255283. These results indicate that the acyl group of the 1,2,4,5 substituted hydroxyacetophenone class of LTB4 antagonists is not critical to antagonist potency. 相似文献
13.
David M. Wilson James Apps Nicholas Bailey Mark J. Bamford Isabel J. Beresford Michael A. Briggs Andrew R. Calver Barry Crook Robert P. Davis Susannah Davis David K. Dean Leanne Harris Tom D. Heightman Terry Panchal Christopher A. Parr Nigel Quashie Jon G.A. Steadman Joanne Schogger Andrew D. Medhurst 《Bioorganic & medicinal chemistry letters》2013,23(24):6897-6901
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties. 相似文献
14.
Zartman CB Bell IM Gallicchio SN Graham SL Kane SA Mallee JJ Rutledge RZ Salvatore CA Vacca JP Williams TM 《Bioorganic & medicinal chemistry letters》2011,21(22):6705-6708
Identification of an HIV integrase inhibitor with micromolar affinity for the CGRP receptor led to the discovery of a series of structurally novel CGRP receptor antagonists. Optimization of this series produced compound 16, a low-molecular weight CGRP receptor antagonist with good pharmacokinetic properties in both rat and dog. In contrast to other nonpeptide antagonists, the activity of 16 was affected by the presence of divalent cations and showed evidence of an alternative, RAMP-independent CGRP receptor binding site. 相似文献
15.
Hall A Atkinson S Brown SH Chessell IP Chowdhury A Giblin GM Goldsmith P Healy MP Jandu KS Johnson MR Michel AD Naylor A Sweeting JA 《Bioorganic & medicinal chemistry letters》2007,17(5):1200-1205
Replacement of the carboxylic acid group in a series of previously described 1,5-biaryl pyrrole EP1 receptor antagonists led to the discovery of various novel non-acidic antagonists. Several analogues displayed high binding affinity and high binding efficiency indices. 相似文献
16.
Dooseop Kim Liping Wang Charles G. Caldwell Ping Chen Paul E. Finke Bryan Oates Malcolm MacCoss Sander G. Mills Lorraine Malkowitz Sandra L. Gould Julie A. DeMartino Martin S. Springer Daria Hazuda Michael Miller Joseph Kessler Renee Danzeisen Gwen Carver Anthony Carella Karen Holmes Janet Lineberger William A. Schleif Emilio A. Emini 《Bioorganic & medicinal chemistry letters》2001,11(24):3099-3102
A series of hydantoin derivatives has been discovered as highly potent nonpeptide antagonists for the human CCR5 receptor. The synthesis, SAR, and biological profiles of this class of antagonists are described. 相似文献
17.
Vuligonda V Standeven AM Escobar M Chandraratna RA 《Bioorganic & medicinal chemistry letters》1999,9(5):743-748
The synthesis and biological activity of a novel series of tricyclic retinoic acid receptor antagonists are described. These compounds bind with high affinity to the RARs and are potent antagonists of retinoid function in in vitro and in vivo systems. 相似文献
18.
Michael J. Sofia William T. Jackson Davis L. SaussyJr. Steven A. Silbaugh Larry L. Froelich Sandra L. Cockerham Peter W. Stengel 《Bioorganic & medicinal chemistry letters》1992,2(12)
A series of
-alkoxyphenols containing a tetrazole acid sidechain have been prepared as antagonists of leukotriene B4 receptors. These compounds were tested as receptor antagonists of human neutrophil and guinea pig lung membrane leukotriene B4 receptors. Compounds in this series were found to be up to 18-fold more potent than LY255283. These results indicate that the acyl group of the 1,2,4,5 substituted hydroxyacetophenone class of LTB4 antagonists is not critical to antagonist potency. 相似文献
19.
Muraglia E Ontoria JM Branca D Dessole G Bresciani A Fonsi M Giuliano C Llauger Bufi L Monteagudo E Palumbi MC Torrisi C Rowley M Steinkühler C Jones P 《Bioorganic & medicinal chemistry letters》2011,21(18):5283-5288
Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies. 相似文献
20.
Nian Zhou Wayne Zeller Michael Krohn Herb Anderson Jun Zhang Emmanuel Onua Alex S. Kiselyov Jose Ramirez Guðrún Halldorsdottir Þorkell Andrésson Mark E. Gurney Jasbir Singh 《Bioorganic & medicinal chemistry letters》2009,19(1):123-126
A series of potent and selective EP3 receptor antagonists are described. Utilizing a pharmacophore model developed for the EP3 receptor, a series of 3,4-disubstituted indoles were shown to be high affinity ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors and are potent antagonists in functional assays. 相似文献