共查询到20条相似文献,搜索用时 15 毫秒
1.
Duffy JL Rano TA Kevin NJ Chapman KT Schleif WA Olsen DB Stahlhut M Rutkowski CA Kuo LC Jin L Lin JH Emini EA Tata JR 《Bioorganic & medicinal chemistry letters》2003,13(15):2569-2572
A biaryl pyridylfuran P(3) substituent on the hydroxyethylene isostere scaffold affords HIV protease inhibitors (PI's) with picomolar (IC(50)) potency against the protease enzymes from PI-resistant HIV-1 strains. Inclusion of a gem-dimethyl substituent afforded compound 3 with 100% oral bioavailability (dogs) and more than double the t(1/2) of indinavir. Inhibition of multiple P450 isoforms is dependent on the regiochemistry of the pyridyl nitrogen in these compounds. 相似文献
2.
4'-Substituted bicyclic pyridones were prepared and evaluated as non-steroidal inhibitors of type 1 and 2 steroid 5alpha-reductase (SR). A range of 4'-substituents were incorporated into the bicyclic scaffold to investigate SAR within and across different classes of non-steroidal inhibitors of SR. Bicyclic pyridones containing a 4'-benzoyl or long carbon chain tether showed more potent inhibition against type 1 SR than inhibitors with N-substituted acetamide groups in the 4'-position. SAR derived from 4'-substituted bicyclic pyridones reported here do not correlate with SAR derived from known potent 4'-substituted biaryl acid SR inhibitors. A 4'-benzoyl group is favoured by the active site in both isozymes. 相似文献
3.
Fringuelli R Schiaffella F Utrilla Navarro MP Milanese L Santini C Rapucci M Marchetti C Riccardi C 《Bioorganic & medicinal chemistry》2003,11(15):3245-3254
We have previously shown 1,4-benzothiazine (1,4-B) derivatives induce thymocyte apoptosis in vitro and thymus cell loss in vivo. Apoptosis is mediated through a complex of biochemical events including phosphatidylcholine specific-phospholipase C (PC-PLC) activation, acidic sphingomyelinase (aSMase) activation and ceramide generation, caspase-8 and caspase-3 activation. As preliminary analysis of the structure-activity relationship (SAR) suggested some structural features were responsible for apoptosis, we synthesised several derivatives and tested for apoptosis activity at equimolar concentrations. In particular, we synthesised analogues that differed in the nature of skeleton (1,4-benzothiazine, 1,4-benzoxazine and 1,2,3,4-tetrahydroquinoline) and in the nature of side chain (imidazole, benzimidazole or piperazine as azole substituent; presence, absence or transformation of alcoholic group). Results of apoptosis induction indicate that transforming the 1,4-benzothiazine skeleton into 1,2,3,4-tetrahydroquinoline does not result in significant change. Transformation into 1,4-benzoxazine decreased activity. Replacing imidazole at the side chain with different piperazines also decreased activity while replacing it with benzimidazole does not change apoptotic activity. Finally, removal of the alcoholic group by dehydration to olefin, or by transforming it into ether, increased activity. Moreover, in an attempt to analyse further the SAR characteristics that are responsible for 1,4-B-activated apoptosis we tested the effect on caspase-8,-9 and-3 activation. 1,4-B analogues activate caspases and the structural requirements correlate with those responsible for apoptosis induction. 相似文献
4.
Marco Schaudt Elsa Locardi Gunther Zischinsky Roland Stragies Jochen R. Pfeifer Christoph Gibson Dirk Scharn Uwe Richter Holger Kalkhof Klaus Dinkel Karsten Schnatbaum 《Bioorganic & medicinal chemistry letters》2010,20(3):1225-1228
The synthesis and SAR of two series of bradykinin B1 receptor antagonists is described. The benzamide moiety proved to be a suitable replacement for the aryl ester functionality of biaryl based antagonists. In addition, it was found that semicarbazides can effectively replace cyclopropyl amino acids. The compounds with the best overall profile were biaryl semicarbazides which display high antagonistic activity, low Caco-2 efflux and high oral bioavailability in the rat. 相似文献
5.
Witter DJ Harrington P Wilson KJ Chenard M Fleming JC Haines B Kral AM Secrist JP Miller TA 《Bioorganic & medicinal chemistry letters》2008,18(2):726-731
A class of biaryl benzamides was identified and optimized as selective HDAC1&2 inhibitors (SHI-1:2). These agents exhibit selectivity over class II HDACs 4-7, as well as class I HDACs 3 and 8; providing examples of selective HDAC inhibitors for the HDAC isoforms most closely associated with cancer. The hypothesis for the increased selectivity is the binding of a pendant aromatic group in the internal cavity of the HDAC1&2 enzymes. SAR development based on an initial lead led to a series of potent and selective inhibitors with reduced off-target activity and tumor growth inhibition activity in a HCT-116 xenograft model. 相似文献
6.
Lunn G Roberts LR Content S Critcher DJ Douglas S Fenwick AE Gethin DM Goodwin G Greenway D Greenwood S Hall K Thomas M Thompson S Williams D Wood G Wylie A 《Bioorganic & medicinal chemistry letters》2012,22(6):2200-2203
3-Azabicyclo[3.1.0]hexane compounds were designed as novel achiral μ opioid receptor ligands for the treatment of pruritus in dogs. In this paper, we describe the SAR of this class of opioid ligand, highlighting changes to the lead structure which led to compounds having picomolar binding affinity, selective for the μ receptor over δ and κ subtypes. Some subtleties of functional activity will also be described. 相似文献
7.
Neil Garton Nick Bailey Mark Bamford Emmanuel Demont Irene Farre-Gutierrez Gail Hutley Gianpaolo Bravi Paula Pickering 《Bioorganic & medicinal chemistry letters》2010,20(3):1049-1054
We report the identification of a novel biaryl template for H+/K+ ATPase inhibition. Evaluation of critical SAR features within the biaryl imidazole framework and the use of pharmacophore modelling against known imidazopyridine and azaindole templates suggested that the geometry of the molecule is key to achieving activity. Herein we present our work optimising the potency of the molecule through modifications and substitutions to each of the ring systems. In particular sub-micromolar potency is achieved with (4b) presumably through a proposed intramolecular hydrogen bond that ensures the required imidazole basic centre is appropriately located. 相似文献
8.
Look GC Vacin C Dias TM Ho S Tran TH Lee LL Wiesner C Fang F Marra A Westmacott D Hromockyj AE Murphy MM Schullek JR 《Bioorganic & medicinal chemistry letters》2004,14(6):1423-1426
Solid-phase synthetic methods for biaryl-based compounds were developed resulting in the construction of two 1000-member libraries. Numerous compounds were identified by high-throughput screening using whole cell screens to exhibit anti-microbial activity against Gram-positive bacteria. A series of biaryl compounds containing natural and unnatural amino acids were made to explore the SAR of the amino acid functionality. 相似文献
9.
Yang SM Scannevin RH Wang B Burke SL Wilson LJ Karnachi P Rhodes KJ Lagu B Murray WV 《Bioorganic & medicinal chemistry letters》2008,18(3):1135-1139
A new series of beta-N-biaryl ether sulfonamide hydroxamates as novel gelatinase inhibitors is described. These compounds exhibit good potency for MMP-2 and MMP-9 without inhibiting MMP-1. The structure-activity relationships (SAR) reveal the biaryl ether type P1' moiety together with methanesulfonamide is the optimal combination that provides inhibitory activity of MMP-9 in the single-digit nanomolar range. 相似文献
10.
Guo T Adang AE Dolle RE Dong G Fitzpatrick D Geng P Ho KK Kultgen SG Liu R McDonald E McGuinness BF Saionz KW Valenzano KJ van Straten NC Xie D Webb ML 《Bioorganic & medicinal chemistry letters》2004,14(7):1713-1716
High-throughput screening of two million compounds in 37 distinct encoded combinatorial libraries using FSH receptor transfected cells provided small molecule agonists such as 1 (EC(50)=3 microM) and 2 (EC(50)=3.9 microM), based on which a focused combinatorial library with a total of 31372 compounds was designed, synthesized, and screened to reveal 72 novel biaryl FSH receptor agonists such as 8a-c as well as a unique combinatorial SAR. 相似文献
11.
Wensheng Yu Ling Tong Seong Heon Kim Michael K.C. Wong Lei Chen De-Yi Yang Bandarpalle B. Shankar Brian J. Lavey Guowei Zhou Aneta Kosinski Razia Rizvi Dansu Li Robert J. Feltz John J. Piwinski Kristin E. Rosner Neng-Yang Shih M. Arshad Siddiqui Zhuyan Guo Peter Orth Himanshu Shah Joseph A. Kozlowski 《Bioorganic & medicinal chemistry letters》2010,20(17):5286-5289
We disclose further optimization of hydantoin TNF-α convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar Ki, good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13. 相似文献
12.
Wang W Devasthale P Wang A Harrity T Egan D Morgan N Cap M Fura A Klei HE Kish K Weigelt C Sun L Levesque P Li YX Zahler R Kirby MS Hamann LG 《Bioorganic & medicinal chemistry letters》2011,21(22):6646-6651
Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 μM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 μmol/kg in ob/ob mice. 相似文献
13.
Mendel D Marquart AL Joseph S Waid P Yee YK Tebbe AL Ratz AM Herron DK Goodson T Masters JJ Franciskovich JB Tinsley JM Wiley MR Weir LC Kyle JA Klimkowski VJ Smith GF Towner RD Froelich LL Buben J Craft TJ 《Bioorganic & medicinal chemistry letters》2007,17(17):4832-4836
SAR about the B-ring of a series of N(2)-aroyl anthranilamide factor Xa (fXa) inhibitors is described. B-ring o-aminoalkylether and B-ring p-amine probes of the S1' and S4 sites, respectively, afforded picomolar fXa inhibitors that performed well in in vitro anticoagulation assays. 相似文献
14.
Twenty-one polyhydroxyphenols, which can all be derived from phloroglucinol, were isolated from Canadian Eisenia arborea (Alariaceae). Most of these compounds contain dibenzo[1,4]dioxin elements and also others benzofuran moieties. The basic component is eckol, a hexahydroxyphenoxydibenzo[1,4]dioxin consisting of three phloroglucinol units. Dioxinodehydroeckol is a benzo[1′,4′]benzodioxino[1,4]benzodioxin derived from eckol. 7,7′-Bieckol, 7,9′-bieckol and 7,2″-bieckol are dimers of eckol with biaryl linkages. 8,4·-Dieckol is a dimeric diphenyl ether. 7-Hydroxyeckol contains one and 7,7′-dihydroxy-9,9′-bieckol two additional hydroxyl groups. 3-Phloroeckol and the dehydro derivatives furodehydroeckol A,B and C are composed of four phloroglucinol rings. Halogenated compounds also occur: monobromo- and monoiodophloroglucinol, 4′-bromo- and 4′-iodoeckol as well as one bromo- and one iodophloroeckol. 相似文献
15.
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
16.
《Bioorganic & medicinal chemistry letters》2014,24(10):2267-2272
The discovery and SAR of a novel series of potent and selective PPARα antagonists are herein described. Exploration of replacements for the labile acyl sulfonamide linker led to a biaryl sulfonamide series of which compound 33 proved to be suitable for further profiling in vivo. Compound 33 demonstrated excellent potency, selectivity against other nuclear hormone receptors, and good pharmacokinetics in mouse. 相似文献
17.
Alan Brown Dave Ellis Olga Wallace Michael Ralph 《Bioorganic & medicinal chemistry letters》2010,20(7):2224-2228
A series of amides were investigated as potential bioisosteres of previously reported triazole Oxytocin antagonists. A range of potent analogues were identified, although SAR for potency and selectivity over the related V1A and V2 receptors was found to be somewhat divergent from that observed for the corresponding triazole series. The high synthetic accessibility of this new amide series also facilitated the identification of a range of alternative left hand side (biaryl replacement) substituents which gave good levels of Oxytocin antagonism. 相似文献
18.
Peptidic 1-cyanopyrrolidines: synthesis and SAR of a series of potent,selective cathepsin inhibitors
Rydzewski RM Bryant C Oballa R Wesolowski G Rodan SB Bass KE Wong DH 《Bioorganic & medicinal chemistry》2002,10(10):3277-3284
1-Cyanopyrrolidines have previously been reported to inhibit cysteinyl cathepsins (Falgueyret, J.-P. et al., J. Med. Chem. 2001, 44, 94). In order to optimize binding interactions for a given cathepsin and simultaneously reduce interactions with the other closely related enzymes, small peptidic substituents were introduced to the 1-cyanopyrrolidine scaffold, either at the 2-position starting with proline or at the 3-position of aminopyrrolidines. The resulting novel compounds proved to be micromolar inhibitors of cathepsin B (Cat B) but nanomolar to picomolar inhibitors of cathepsins K, L, and S (Cat K, Cat L, Cat S). Several of the compounds were >20-fold selective versus the other three cathepsins. SAR trends were observed, most notably the remarkable potency of Cat L inhibitors based on the 1-cyano-D-proline scaffold. The selectivity of one such compound, the 94 picomolar Cat L inhibitor 12, was demonstrated at higher concentrations in DLD-1 cells. Although none of the compounds in the proline series that was tested proved to be submicromolar in the in vitro bone resorption assay, two Cat K inhibitors in the 3-substituted pyrrolidine series, 24 and 25 were relatively potent in that assay. 相似文献
19.
Achieving multi-isoform PI3K inhibition in a series of substituted 3,4-dihydro-2H-benzo[1,4]oxazines
Perry B Alexander R Bennett G Buckley G Ceska T Crabbe T Dale V Gowers L Horsley H James L Jenkins K Crépy K Kulisa C Lightfoot H Lock C Mack S Morgan T Nicolas AL Pitt W Sabin V Wright S 《Bioorganic & medicinal chemistry letters》2008,18(16):4700-4704
The SAR and pharmacokinetic profiles of a series of multi-isoform PI3K inhibitors based on a 3,4-dihydro-2H-benzo[1,4]oxazine scaffold are disclosed. 相似文献
20.
Sara Cesarini Andrea Spallarossa Angelo Ranise Olga Bruno Nicoletta Arduino Maria Bertolotto Franco Dallegri Massimiliano Tognolini Thomas Gobbetti Elisabetta Barocelli 《Bioorganic & medicinal chemistry》2009,17(10):3580-3587
A series of 6-amino-4-oxo-1,3-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl derivatives was synthesized. The compounds demonstrated to be novel, potent and selective inhibitors of Interleukin-8-induced human neutrophil chemotaxis. A SAR study was performed by varying the carbonyl function at position 5 and the chain linked to the amino group at position 6 of the scaffold. All the compounds of the series displayed inhibitory activity at nano- or picomolar concentrations against Interleukin-8-driven migration and no activity against fMLP- and C5a-induced chemotaxis. The binding tests of selected compounds on CXCR1 and CXCR2 receptors were negative. The most potent derivative showed in vivo efficacy in a mouse model of Zymosan-induced peritonitis. 相似文献