共查询到20条相似文献,搜索用时 0 毫秒
1.
Bodmer-Narkevitch V Anthony NJ Cofre V Jolly SM Murphy KL Ransom RW Reiss DR Tang C Prueksaritanont T Pettibone DJ Bock MG Kuduk SD 《Bioorganic & medicinal chemistry letters》2010,20(23):7011-7014
A new class of indazole-derived bradykinin B(1) antagonists and their structure-activity relationships (SAR) is reported. A number of compounds were found to have low-nanomolar affinity for the human B(1) receptor and possess acceptable P-gp and pharmacokinetics properties. 相似文献
2.
Chen JJ Qian W Biswas K Viswanadhan VN Askew BC Hitchcock S Hungate RW Arik L Johnson E 《Bioorganic & medicinal chemistry letters》2008,18(16):4477-4481
Replacement of the core beta-amino acid in our previously reported piperidine acetic acid and beta-phenylalanine-based Bradykinin B1 antagonists by dihydroquinoxalinone acetic acid increases the in vitro potency and metabolic stability. The most potent compounds from this series have IC(50)s<0.2 nM in a human B1 receptor functional assay. A molecular modeling study of the binding modes of key compounds, based on a B1 homology model, explains the structure-activity relationship (SAR) for these analogs. 相似文献
3.
Andrew G. Cole Axel Metzger Marc-Raleigh Brescia Lan-Ying Qin Kenneth C. Appell Christopher T. Brain Allan Hallett Pam Ganju Alastair A. Denholm James R. Wareing Timothy J. Ritchie Gillian M. Drake Stuart J. Bevan Aisling MacGloinn Andrew McBryde Viral Patel Paul J. Oakley Ximena Nunez Hubert Gstach Peter Schneider Ian Henderson 《Bioorganic & medicinal chemistry letters》2009,19(1):119-122
The synthesis and identification of sulfonamido-aryl ethers as potent bradykinin B1 receptor antagonists from a ~60,000 member encoded combinatorial library are reported. Two distinct series of compounds exhibiting different structure–activity relationships were identified in a bradykinin B1 whole-cell receptor-binding assay. Specific examples exhibit Ki values of ~10 nM. 相似文献
4.
Eles J Beke G Vágó I Bozó E Huszár J Tarcsay A Kolok S Schmidt E Vastag M Hornok K Farkas S Domány G Keserű GM 《Bioorganic & medicinal chemistry letters》2012,22(9):3095-3099
A new series of quinolinyl- and phenantridinyl-acetamides were synthesizer and evaluated against bradykinin B1 receptor. In vitro metabolic stability data were reported for the key compounds.The analgesic effect of compound 20 from the phenantridine series was proved in-vivo. 相似文献
5.
Chen JJ Nguyen T D'Amico DC Qian W Human J Aya T Biswas K Fotsch C Han N Liu Q Nishimura N Peterkin TA Yang K Zhu J Riahi BB Hungate RW Andersen NG Colyer JT Faul MM Kamassah A Wang J Jona J Kumar G Johnson E Askew BC 《Bioorganic & medicinal chemistry letters》2011,21(11):3384-3389
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC50 of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described. 相似文献
6.
Biswas K Aya T Qian W Peterkin TA Chen JJ Human J Hungate RW Kumar G Arik L Lester-Zeiner D Biddlecome G Manning BH Sun H Dong H Huang M Loeloff R Johnson EJ Askew BC 《Bioorganic & medicinal chemistry letters》2008,18(17):4764-4769
We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to compound 26, both of which were efficacious in rabbit biochemical challenge and pain models. 相似文献
7.
Wood MR Schirripa KM Kim JJ Kuduk SD Chang RK Di Marco CN DiPardo RM Wan BL Murphy KL Ransom RW Chang RS Holahan MA Cook JJ Lemaire W Mosser SD Bednar RA Tang C Prueksaritanont T Wallace AA Mei Q Yu J Bohn DL Clayton FC Adarayn ED Sitko GR Leonard YM Freidinger RM Pettibone DJ Bock MG 《Bioorganic & medicinal chemistry letters》2008,18(2):716-720
Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure. 相似文献
8.
Bryan MC Biswas K Peterkin TA Rzasa RM Arik L Lehto SG Sun H Hsieh FY Xu C Fremeau RT Allen JR 《Bioorganic & medicinal chemistry letters》2012,22(1):619-622
A series of fused 6,6-bicyclic chromenones was investigated for activity against the bradykinin B1 receptor. SAR studies based on a pharmacophore model revealed compounds with high affinity for both human and rabbit B1. These compounds demonstrated favorable pharmacokinetic properties and 5-chlorochromenone 15 was efficacious in a carrageenan-induced mechanical hyperalgesia model for chronic pain. 相似文献
9.
《Bioorganic & medicinal chemistry》2016,24(19):4675-4691
A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF1 receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles. The novel synthesis of 7-arylaminobenzimidazoles culminated in the identification of compounds exhibiting inhibitory activities comparable to the alkyl analog 1. A representative compound, p-methoxyanilino analog 16g, showed potent CRF binding inhibitory activity against a human CRF1 receptor and human CRF1 receptor antagonistic activity (IC50 = 27 nM, 56 nM, respectively). This compound exhibited ex vivo 125I-Tyr0 (125I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20 mg/kg after oral administration. In this report, we discuss the structure–activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method. 相似文献
10.
Makoto Ando Etsuko Sekino Yuji Haga Minoru Moriya Masahiko Ito Junko Ito Hisashi Iwaasa Akane Ishihara Akio Kanatani Norikazu Ohtake 《Bioorganic & medicinal chemistry letters》2009,19(17):5186-5190
Novel phenethylpyridone derivatives were identified as potent human melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. A search for surrogates for the 4-(2-aminoethoxy)phenyl moiety of 1 resulted in discovery of 2-[4-(aminomethyl)phenyl]ethyl substructure as in 6a. Successive optimization of the right-hand moiety led to the identification of a number of potent derivatives. 相似文献
11.
Morley AD Cook A King S Roberts B Lever S Weaver R Macdonald C Unitt J Fagura M Phillips T Lewis R Wenlock M 《Bioorganic & medicinal chemistry letters》2011,21(21):6456-6460
A series of pyrazole inhibitors of the human FPR1 receptor have been identified from high throughput screening. The compounds demonstrate potent inhibition in human neutrophils and attractive physicochemical and in vitro DMPK profiles to be of further interest. 相似文献
12.
Hall A Bit RA Brown SH Chaignot HM Chessell IP Coleman T Giblin GM Hurst DN Kilford IR Lewell XQ Michel AD Mohamed S Naylor A Novelli R Skinner L Spalding DJ Tang SP Wilson RJ 《Bioorganic & medicinal chemistry letters》2006,16(10):2666-2671
We describe the generation of novel EP(1) receptor antagonists by investigation of thiophene isosteres. In addition, we disclose preliminary in vitro and in vivo DMPK for selected compounds. 相似文献
13.
Guo Q Chandrasekhar J Ihle D Wustrow DJ Chenard BL Krause JE Hutchison A Alderman D Cheng C Cortright D Broom D Kershaw MT Simmermacher-Mayer J Peng Y Hodgetts KJ 《Bioorganic & medicinal chemistry letters》2008,18(18):5027-5031
The design, synthesis, and structure-activity studies of a novel series of BK B(1) receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B(1) receptor were discovered. 相似文献
14.
Zhong-Yue Sun Zhaoning Zhu Yuanzan Ye Brian McKittrick Michael Czarniecki William Greenlee Deborra Mullins Mario Guzzi 《Bioorganic & medicinal chemistry letters》2009,19(23):6801-6805
A class of novel 2-aminobenzothiazoles have been identified as NPY Y1 antagonists. Various N-heterocyclic substituted aminophenethyl-2-aminobenzothiazole analogs were synthesized to explore the SAR. Isothiourea analogs and ligands with high potency (Ki 30 nM) have been identified. 相似文献
15.
Miskolzie M Gera L Stewart JM Kotovych G 《Journal of biomolecular structure & dynamics》2002,19(4):585-593
The secondary structure of a bradykinin B(1)receptor antagonist B-10324 (F5C-Lys-(1)- Lys(0)-Arg(1)-Pro(2)- Hyp(3)-Gly(4)-CpG(5)- Ser(6)-DTic(7)-CpG(8)) was determined by NMR at 800MHz. The conformational data are compared with those obtained previously for two bradykinin B(1) receptor antagonists, namely B-9858 (Lys-(1)- Lys(0)-Arg(1)-Pro(2)- Hyp(3)-Gly(4)-Igl(5)- Ser(6)-DIgl(7)-Oic(8)) and B-10148 (Lys-(1)-Lys(0)-Arg(1)- Pro(2)-Hyp(3)-Gly(4)- Igl(5)-Ser(6)-DF5F(7)- Oic(8)). The abnormal amino acids are: Hyp, trans-4- hydroxyproline; Tic, 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid; Oic, (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid; Igl, alpha(2- indanyl)glycine; F5F, 2,3,4,5,6-pentafluorophenylalanine; CpG, alpha- cyclopentylglycine. F5C, pentafluorocinnamoyl, is the N-terminal protecting group and is not involved in the peptide secondary structure. B-10324 contains an N-terminal Pro(2)- CpG(5) distorted type II beta-turn whereas the rest of the peptide is random. A salt bridge is not observed between the carboxylate group at the C-terminal end and the Arg(1) side chain, in contrast to that previously observed for B-9858 and B- 10148. The conformations are correlated with the measured B(1) receptor antagonist activities (J.-F. Larrivée, L. Gera, S. Houle, J. Bouthillier, D. R. Bachvarov, J. M. Stewart and F. Marc au, Br. J. Pharmacol. 131, 885-892 (2000)). The importance of the N-terminal beta-turn is highlighted. 相似文献
16.
Large species differences have been previously observed in the pharmacology of bradykinin (BK) B2 receptor antagonists. We investigated the effect of two novel non-peptide antagonists, compound 9 (a benzodiazepine peptidomimetic related to icatibant) and the thiosemicarbazide bradyzide on the rabbit B2 receptor (contractility of the jugular vein, competition of [3H]BK binding to a B2 receptor-green fluorescent protein (B2R-GFP) conjugate, subcellular distribution of B2R-GFP). While compound 9 is about 9000-fold less potent than icatibant, it shares with the latter peptide drug a selective, insurmountable and largely irreversible antagonist behavior against BK and the capacity to translocate B2R-GFP from the membrane into the cells. Bradyzide, reportedly very potent at rodent B2 receptors, was a competitive and reversible antagonist of moderate potency at the rabbit B2 receptor (contractility pA2 6.84, binding competition IC50 5 nM). The C-terminal region of icatibant, reproduced by compound 9, is likely to be important in the non-equilibrium behavior of icatibant. Bradyzide, a non-peptide antagonist developed on different structural grounds, is competitive at the rabbit B2 receptor. 相似文献
17.
Su DS Lim JL Markowitz MK Wan BL Murphy KL Reiss DR Harrell CM O'Malley SS Ransom RW Chang RS Pettibone DJ Tang C Prueksaritanont T Freidinger RM Bock MG 《Bioorganic & medicinal chemistry letters》2007,17(11):3006-3009
Selective bradykinin (BK) B(1) receptor antagonists have been shown to be antinociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure-activity relationships of the biphenyl moiety of the lead compound 1 provided a potent new structural class of BK B(1) receptor antagonists. 相似文献
18.
Qingyian Liu Wenyuan Qian Aiwen Li Kaustav Biswas Jian Jeffrey Chen Christopher Fotsch Nianhe Han Chester Yuan Leyla Arik Gloria Biddlecome Eileen Johnson Gondi Kumar Dianna Lester-Zeiner Gordon Y. Ng Randall W. Hungate Benny C. Askew 《Bioorganic & medicinal chemistry letters》2010,20(15):4593-4597
The bradykinin B1 receptor has been shown to mediate pain response and is rapidly induced upon injury. Blocking this receptor may provide a promising treatment for inflammation and pain. We previously reported tetralin benzyl amines as potent B1 antagonists. Here we describe the synthesis and SAR of B1 receptor antagonists with homobenzylic amines. The SAR of different linkers led to the discovery of tetralin allylic amines as potent and selective B1 receptor antagonists (hB1 IC50 = 1.3 nM for compound 16). Some of these compounds showed modest oral bioavailability in rats. 相似文献
19.
Feng DM Wai JM Kuduk SD Ng C Murphy KL Ransom RW Reiss D Chang RS Harrell CM MacNeil T Tang C Prueksaritanont T Freidinger RM Pettibone DJ Bock MG 《Bioorganic & medicinal chemistry letters》2005,15(9):2385-2388
A novel class of 2,3-diaminopyridine bradykinin B1 receptor antagonists is disclosed. Structure-activity relationship studies (SARs) that led to compounds with significantly improved potency and pharmacokinetic properties relative to the lead compound are described. 相似文献
20.
Gavai AV Vaz RJ Mikkilineni AB Roberge JY Liu Y Lawrence RM Corte JR Yang W Bednarz M Dickson JK Ma Z Seethala R Feyen JH 《Bioorganic & medicinal chemistry letters》2005,15(24):1225-5482
A 3D quantitative structure–activity relationship study for inhibition of calcium-sensing receptor in the aryloxypropanolamine series predicted that these molecules adopt a U-shaped conformation with pi-stacking between the two aromatic rings. This hypothesis led to the discovery of novel 1-arylmethyl pyrrolidin-2-yl ethanol amines capable of antagonizing the calcium-sensing receptor with potency comparable to that of NPS-2143. 相似文献