共查询到20条相似文献,搜索用时 15 毫秒
1.
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
2.
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
3.
Perkins JJ Duong LT Fernandez-Metzler C Hartman GD Kimmel DB Leu CT Lynch JJ Prueksaritanont T Rodan GA Rodan SB Duggan ME Meissner RS 《Bioorganic & medicinal chemistry letters》2003,13(24):4285-4288
Antagonists of the integrin receptor alpha(v)beta(3) are expected to have utility in the treatment of osteoporosis through inhibition of bone resorption. A series of potent, chain-shortened, pyrrolidinone-containing alpha(v)beta(3) receptor antagonists is described. Two sets of diasteromeric pairs of high-affinity antagonists demonstrated marked differences in log P values, which translated into differing dog pharmacokinetic properties. One member of this set was demonstrated to be effective in reducing bone resorption in rats. 相似文献
4.
Zartman AE Duong le T Fernandez-Metzler C Hartman GD Leu CT Prueksaritanont T Rodan GA Rodan SB Duggan ME Meissner RS 《Bioorganic & medicinal chemistry letters》2005,15(6):1647-1650
Potent, novel 7-oxo alpha(v)beta3 antagonists have been prepared. These antagonists offer decreased plasma protein binding and excellent pharmacokinetic profiles. 相似文献
5.
Ishikawa M Kubota D Yamamoto M Kuroda C Iguchi M Koyanagi A Murakami S Ajito K 《Bioorganic & medicinal chemistry》2006,14(7):2109-2130
We synthesized 4-aminopiperidine derivatives of our prototype integrin alpha(v)beta3 antagonist 1 in an attempt to increase the activity and water solubility. Introduction of one or two hydrophilic moieties into the central aromatic ring and/or the benzene ring at the C-terminus of 1 increased water solubility and enhanced inhibition of cell adhesion. The results of a structure-activity relationships (SAR) study indicated that the torsion angle between the central aromatic ring and the piperidine ring, and the acidity at the sulfonamide moiety, might be important for alpha(v)beta3 receptor binding activity. Some of these compounds are novel and potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile. 相似文献
6.
Wang J Breslin MJ Coleman PJ Duggan ME Hunt CA Hutchinson JH Leu CT Rodan SB Rodan GA Duong le T Hartman GD 《Bioorganic & medicinal chemistry letters》2004,14(4):1049-1052
A series of 3-substituted tetrahydro-[1,8]naphthyridine containing alpha(v)beta(3) antagonists was prepared. A comparison of their in vitro IC(50) values to the electron properties of the 3-substituents revealed a good linear Hammett correlation (rho=-1.96, R(2)=0.959). Electron-withdrawing groups at the 3-position of the tetrahydro-[1,8]naphthyridine decreased potency while electron-donating groups enhanced potency. 相似文献
7.
Ishikawa M Hiraiwa Y Kubota D Tsushima M Watanabe T Murakami S Ouchi S Ajito K 《Bioorganic & medicinal chemistry》2006,14(7):2131-2150
In order to optimize our novel integrin alpha(v)beta3/alpha(IIb)beta3 dual antagonists, spatial screening at the N-terminus was performed. The alpha(v)beta3 antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against alpha(IIb)beta3 was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against alpha(v)beta3, and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the alpha(v)beta3 receptor were performed to confirm the SAR findings. 相似文献
8.
Robert S Meissner James J Perkins Le T Duong George D Hartman William F Hoffman Joel R Huff Nathan C Ihle Chih Tai Leu Rose M Nagy Adel Naylor-Olsen Gideon A Rodan Sevgi B Rodan David B Whitman Gregg A Wesolowski Mark E Duggan 《Bioorganic & medicinal chemistry letters》2002,12(1):25-29
Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, alpha(v)beta(3). The use of the 5,6,7,8-tetrahydro[1,8]naphthyridine group as a potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in alpha(IIb)beta(3) antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints. 相似文献
9.
Penning TD Khilevich A Chen BB Russell MA Boys ML Wang Y Duffin T Engleman VW Finn MB Freeman SK Hanneke ML Keene JL Klover JA Nickols GA Nickols MA Rader RK Settle SL Shannon KE Steininger CN Westlin MM Westlin WF 《Bioorganic & medicinal chemistry letters》2006,16(12):3156-3161
We describe a series of pyrazole and isoxazole analogs as antagonists of the alpha(v)beta3 receptor. Compounds showed low to sub-nanomolar potency against alpha(v)beta3, as well as good selectivity against alpha(IIb)beta3. In HT29 cells, most analogs also demonstrated significant selectivity against alpha(v)beta6. Several compounds showed good pharmacokinetic properties in rats, in addition to anti-angiogenic activity in a mouse corneal micropocket model. Compounds were synthesized in a straightforward manner from readily available glutarate precursors. 相似文献
10.
Kubota D Ishikawa M Yamamoto M Murakami S Hachisu M Katano K Ajito K 《Bioorganic & medicinal chemistry》2006,14(7):2089-2108
In order to generate novel compounds with integrin alpha(v)beta3-antagonistic activity together with antiplatelet activity, tricyclic pharmacophore-based molecules were designed and synthesized. Although piperazine-containing compounds initially prepared were selective alpha(IIb)beta3 antagonists, replacement of piperazine with piperidine furnished a potent alpha(v)beta3/alpha(IIb)beta3 dual antagonist. Structure-activity relationship (SAR) studies provided clues for further development of tricyclic pharmacophore-based integrin antagonists. 相似文献
11.
Peyman A Wehner V Knolle J Stilz HU Breipohl G Scheunemann KH Carniato D Ruxer JM Gourvest JF Gadek TR Bodary S 《Bioorganic & medicinal chemistry letters》2000,10(2):179-182
The synthesis of a series of RGD mimetic alpha(v)beta3 antagonists containing a hydantoin scaffold is shown. The results demonstrate some of the structural requirements for the design of selective alpha(v)beta3 antagonists (vs alpha(IIb)beta3) in terms of the Arg-mimetic, the distance between N- and C-terminus and the lipophilic side chain. 相似文献
12.
Penning TD Russell MA Chen BB Chen HY Desai BN Docter SH Edwards DJ Gesicki GJ Liang CD Malecha JW Yu SS Engleman VW Freeman SK Hanneke ML Shannon KE Westlin MM Nickols GA 《Bioorganic & medicinal chemistry letters》2004,14(6):1471-1476
We describe a series of conformationally-restricted cinnamic acid peptidomimetics as well as several cinnamic acid isosteres, including 3-phenylpropionic acids, 2-amino-3-phenylpropionic acids, phenoxyacetic acids and 2-phenylcyclopropylcarboxylic acids. Several analogues demonstrated low to sub-nanomolar potencies against alpha(v)beta(3) and greater than 200-fold selectivity against the other beta(3) integrin alpha(IIb)beta(3). In whole 293 cells, many of these analogues also showed modest selectivity against other alpha(v) integrins such as alpha(v)beta(1) and alpha(v)beta(5). These compounds were synthesized from readily available starting materials using either Heck or Mitsunobu coupling conditions. 相似文献
13.
Leonard K Pan W Anaclerio B Gushue JM Guo Z DesJarlais RL Chaikin MA Lattanze J Crysler C Manthey CL Tomczuk BE Marugan JJ 《Bioorganic & medicinal chemistry letters》2005,15(10):2679-2684
We describe the synthesis and structure/activity relationship of RGD mimetics that are potent inhibitors of the integrin alpha(v)beta3. Indol-1-yl propionic acids containing a variety of basic moieties at the 5-position, as well as substitutions alpha and beta to the carboxy terminus were synthesized and evaluated. Novel compounds with improved potency have been identified. 相似文献
14.
Wendt JA Wu H Stenmark HG Boys ML Downs VL Penning TD Chen BB Wang Y Duffin T Finn MB Keene JL Engleman VW Freeman SK Hanneke ML Shannon KE Nickols MA Steininger CN Westlin M Klover JA Westlin W Nickols GA Russell MA 《Bioorganic & medicinal chemistry letters》2006,16(4):845-849
We describe a series of 2,5 thiazole containing compounds, which are potent antagonists of the integrin alpha(v)beta3 and show selectivity relative to the other integrins, such as alpha(IIb)beta3 and alpha(v)beta6. These analogs were demonstrated to have high bioavailability relative to other relative heterocyclic analogs. 相似文献
15.
Boys ML Schretzman LA Chandrakumar NS Tollefson MB Mohler SB Downs VL Penning TD Russell MA Wendt JA Chen BB Stenmark HG Wu H Spangler DP Clare M Desai BN Khanna IK Nguyen MN Duffin T Engleman VW Finn MB Freeman SK Hanneke ML Keene JL Klover JA Nickols GA Nickols MA Steininger CN Westlin M Westlin W Yu YX Wang Y Dalton CR Norring SA 《Bioorganic & medicinal chemistry letters》2006,16(4):839-844
We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin alpha(v)beta3 and, in addition, show selectivity relative to the other beta3 integrin alpha(IIb)beta3. In whole cells, the majority of these analogs also demonstrated modest selectivity against other alpha(v) integrins such as alpha(v)beta1 and alpha(v)beta6. 相似文献
16.
Perron-Sierra F Saint Dizier D Bertrand M Genton A Tucker GC Casara P 《Bioorganic & medicinal chemistry letters》2002,12(22):3291-3296
A novel series of potent and specific alpha(v) integrin antagonists has been obtained by aminoalkyl substitutions on benzocyloheptene acetic acids as a rigid GD bioisostere. The preferred compounds 1-2, 1-3 and 1-8, showed nano- to subnanomolar IC(50) values on alpha(v)beta(3) and alpha(v)beta(5) integrins, with favorable pharmacokinetics. 相似文献
17.
Kling A Backfisch G Delzer J Geneste H Graef C Holzenkamp U Hornberger W Lange UE Lauterbach A Mack H Seitz W Subkowski T 《Bioorganic & medicinal chemistry letters》2002,12(3):441-446
Synthesis and SARs of new integrin alpha(V)beta(3) antagonists based on an N-substituted dibenzazepinone scaffold are described. Variation of spacer and guanidine mimetic led to potent compounds exhibiting an IC(50) towards alpha(V)beta(3) in the nanomolar range, high selectivity versus integrin alpha(IIb)beta(3) and efficacy in functional cellular assays. 相似文献
18.
Bregman H Nguyen HN Feric E Ligutti J Liu D McDermott JS Wilenkin B Zou A Huang L Li X McDonough SI Dimauro EF 《Bioorganic & medicinal chemistry letters》2012,22(5):2033-2042
Herein the discovery of a novel class of aminoheterocyclic Na(v)1.7 antagonists is reported. Hit compound 1 was potent but suffered from poor pharmacokinetics and selectivity. The compact structure of 1 offered a modular synthetic strategy towards a broad structure-activity relationship analysis. This analysis led to the identification of aminopyrazine 41, which had vastly improved hERG selectivity and pharmacokinetic properties. 相似文献
19.
G Müller M Albers R Fischer G Hessler T E Lehmann H Okigami M Tajimi K Bacon T R?lle 《Bioorganic & medicinal chemistry letters》2001,11(23):3019-3021
Piperidinyl carboxylic acid-based derivatives were prepared as antagonists of the leukocyte cell adhesion process that is mediated through the interaction of the alpha(4)beta(1) integrin (VLA-4, very late antigen 4) and the vascular cell adhesion molecule 1 (VCAM-1). Compounds 2a-h inhibited the adhesion in a cell-based assay in the low and sub micromolar range, a pharmacokinetic study of 2d is reported. 相似文献
20.
Urbahns K Härter M Albers M Schmidt D Stelte-Ludwig B Brüggemeier U Vaupel A Keldenich J Lustig K Tsujishita H Gerdes C 《Bioorganic & medicinal chemistry letters》2007,17(22):6151-6154
Vitronectin receptor (alpha(V)beta(3)) antagonists have been implicated as a possible new treatment of restenosis following balloon angioplasty. In this work we investigate a series of novel arginine mimetic scaffolds leading to new insight of the alpha(V)beta(3)/ligand interaction. Squaric acid amide 10 is a subnanomolar alpha(V)beta(3) antagonist with improved potency on human smooth muscle cell migration. 相似文献