共查询到20条相似文献,搜索用时 31 毫秒
1.
Watson NS Adams C Belton D Brown D Burns-Kurtis CL Chaudry L Chan C Convery MA Davies DE Exall AM Harling JD Irvine S Irving WR Kleanthous S McLay IM Pateman AJ Patikis AN Roethke TJ Senger S Stelman GJ Toomey JR West RI Whittaker C Zhou P Young RJ 《Bioorganic & medicinal chemistry letters》2011,21(6):1588-1592
The discovery and evaluation of potent and long-acting oral sulfonamidopyrrolidin-2-one factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs are described. Unexpected selectivity issues versus tissue plasminogen activator in the former series were addressed in the later, delivering a robust candidate for progression towards clinical studies. 相似文献
2.
D Beattie D Beer ME Bradley I Bruce SJ Charlton BM Cuenoud RA Fairhurst D Farr JR Fozard D Janus EM Rosethorne DA Sandham DA Sykes A Trifilieff KL Turner E Wissler 《Bioorganic & medicinal chemistry letters》2012,22(19):6280-6285
The synthesis of a series of indacaterol analogues in which each of the three structural regions of indacaterol are modified in a systematic manner is described. Evaluation of the affinity of these analogues for the β(2)-adrenoceptor identified the 3,4-dihydroquinolinone and 5-n-butylindanyl analogues to demonstrate the most similar profiles to indacaterol. An α-methyl aminoindane analogue was discovered to be 25-fold more potent than indacaterol, and functional studies revealed an atypical β(2)-adrenoceptor activation profile for this compound consistent with that of a slowly dissociating 'super agonist'. 相似文献
3.
Matthews JM Chen X Cryan E Hlasta DJ Rybczynski PJ Strauss K Tang Y Xu JZ Yang M Zhou L Demarest KT 《Bioorganic & medicinal chemistry letters》2007,17(24):6773-6778
A series of aminoindane derivatives were synthesized and shown to be potent PPARα agonists. The compounds were obtained as racemates in 12 steps, and tested for PPARα activation and PPARα mediated induction of the HD gene. SAR was developed by variation to the core structure as shown within. Oral bioavailability was demonstrated in a Sprague–Dawley rat, while efficacy to reduce plasma triglycerides and plasma glucose was demonstrated in db/db mice. 相似文献
4.
Darin J. Gustin Yihong Li Matthew L. Brown Xiaoshan Min Mike J. Schmitt Malgorzata Wanska Xiaodong Wang Richard Connors Sheere Johnstone Mario Cardozo Alan C. Cheng Shawn Jeffries Brendon Franks Shyun Li Shanling Shen Mariwil Wong Holger Wesche Guifen Xu Zhulun Wang 《Bioorganic & medicinal chemistry letters》2013,23(16):4608-4616
Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other’s loss. Thus, inhibition of both isoforms is likely required to block SphK dependent angiogenesis. A structure based approach was used to design and synthesize a series of SphK inhibitors resulting in the identification of the first potent inhibitors of both isoforms of human SphK. Additionally, to our knowledge, this series of inhibitors contains the only sufficiently potent inhibitors of murine SphK1 with suitable physico-chemical properties to pharmacologically interrogate the role of SphK1 in rodent models and to reproduce the phenotype of SphK1 (?/?) mice. 相似文献
5.
Chatterjee AK Liu H Tully DC Guo J Epple R Russo R Williams J Roberts M Tuntland T Chang J Gordon P Hollenbeck T Tumanut C Li J Harris JL 《Bioorganic & medicinal chemistry letters》2007,17(10):2899-2903
Peptidic, non-covalent inhibitors of lysosomal cysteine protease cathepsin S (1 and 2) were investigated due to low oral bioavailability, leading to an improved series of peptidomimetic inhibitors. Utilizing phenyl succinamides as the P2 residue increased the oral exposure of this lead series of compounds, while retaining selective inhibition of the cathepsin S isoform. Concurrent investigation of the P1 and P2 subsites resulted in the discovery of several potent and selective inhibitors of cathepsin S with good pharmacokinetic properties due to the elimination of saturated aliphatic P2 residues. 相似文献
6.
Savvas Kleanthous Alan D. Borthwick David Brown Cynthia L. Burns-Kurtis Matthew Campbell Laiq Chaudry Chuen Chan Marie-Olive Clarte Máire A. Convery John D. Harling Eric Hortense Wendy R. Irving Stephanie Irvine Anthony J. Pateman Angela N. Patikis Ivan L. Pinto Derek R. Pollard Theresa J. Roethka Stefan Senger Gita P. Shah Robert J. Young 《Bioorganic & medicinal chemistry letters》2010,20(2):618-622
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series. 相似文献
7.
A series of noncovalent tripeptidic thrombin inhibitors incorporating a unidazolylethynyl moiety at P1 was investigated. A number of compounds of this series were highly potent and selective versus trypsin, and several compounds demonstrated good oral absorption in rats (F=58% for compound 19). 相似文献
8.
Bin Ma Kevin M. Guckian Edward Yin-Shiang Lin Wen-Cherng Lee Daniel Scott Gnanasambandam Kumaravel Timothy L. Macdonald Kevin R. Lynch Cheryl Black Sowmya Chollate Kyungmin Hahm Gregg Hetu Ping Jin Yi Luo Ellen Rohde Anthony Rossomando Robert Scannevin Joy Wang Chunhua Yang 《Bioorganic & medicinal chemistry letters》2010,20(7):2264-2269
Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (?)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability. 相似文献
9.
Luigi Piero Stasi Roberto Artusi Clara Bovino Benedetta Buzzi Luca Canciani Gianfranco Caselli Fabrizio Colace Paolo Garofalo Silvia Giambuzzi Patrice Larger Ornella Letari Stefano Mandelli Lorenzo Perugini Sabrina Pucci Matteo Salvi PierLuigi Toro 《Bioorganic & medicinal chemistry letters》2013,23(9):2653-2658
Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats. 相似文献
10.
Vendeville S Nilsson M de Kock H Lin TI Antonov D Classon B Ayesa S Ivanov V Johansson PO Kahnberg P Eneroth A Wikstrom K Vrang L Edlund M Lindström S Van de Vreken W McGowan D Tahri A Hu L Lenz O Delouvroy F Van Dooren M Kindermans N Surleraux D Wigerinck P Rosenquist A Samuelsson B Simmen K Raboisson P 《Bioorganic & medicinal chemistry letters》2008,18(23):6189-6193
A novel series of P3-truncated macrocyclic HCV NS3/4A protease inhibitors containing a P2 proline-urea or carbamate scaffold was synthesized. Very potent inhibitors were obtained through the optimization of the macrocycle size, urea and proline substitution, and bioisosteric replacement of the P1 carboxylic acid moiety. Variation of the lipophilicity by introduction of small lipophilic substituents resulted in improved PK profiles, ultimately leading to compound 13Bh, an extremely potent (K(i)=0.1 nM, EC(50)=4.5 nM) and selective (CC(50) (Huh-7 cells)>50 microM) inhibitor, displaying an excellent PK profile in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration. 相似文献
11.
Watson NS Brown D Campbell M Chan C Chaudry L Convery MA Fenwick R Hamblin JN Haslam C Kelly HA King NP Kurtis CL Leach AR Manchee GR Mason AM Mitchell C Patel C Patel VK Senger S Shah GP Weston HE Whitworth C Young RJ 《Bioorganic & medicinal chemistry letters》2006,16(14):3784-3788
A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species. 相似文献
12.
Greenspan PD Clark KL Cowen SD McQuire LW Tommasi RA Farley DL Quadros E Coppa DE Du Z Fang Z Zhou H Doughty J Toscano KT Wigg AM Zhou S 《Bioorganic & medicinal chemistry letters》2003,13(22):4121-4124
To improve the pharmacokinetics of a previously reported series of dipeptidyl nitrile cathepsin B inhibitors, the P(2)-P(3) amide group was replaced with an arylamine. Further optimization of this template resulted in highly potent and selective inhibitors with excellent oral availability. 相似文献
13.
Kohrt JT Filipski KJ Cody WL Bigge CF La F Welch K Dahring T Bryant JW Leonard D Bolton G Narasimhan L Zhang E Peterson JT Haarer S Sahasrabudhe V Janiczek N Desiraju S Hena M Fiakpui C Saraswat N Sharma R Sun S Maiti SN Leadley R Edmunds JJ 《Bioorganic & medicinal chemistry》2006,14(13):4379-4392
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability. 相似文献
14.
15.
Alessandro A. Boezio Loren Berry Brian K. Albrecht David Bauer Steven F. Bellon Christiane Bode April Chen Deborah Choquette Isabelle Dussault Satoko Hirai Paula Kaplan-Lefko Jay F. Larrow Min-Hwa Jasmine Lin Julia Lohman Michele H. Potashman Karen Rex Michael Santostefano Kavita Shah Roman Shimanovich Stephanie K. Springer Yohannes Teffera Yajing Yang Yihong Zhang Jean-Christophe Harmange 《Bioorganic & medicinal chemistry letters》2009,19(22):6307-6312
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22 days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model. 相似文献
16.
Barrett DG Catalano JG Deaton DN Long ST Miller LR Tavares FX Wells-Knecht KJ Wright LL Zhou HQ 《Bioorganic & medicinal chemistry letters》2004,14(10):2543-2546
An orally available series of ketoamide-based inhibitors of cathepsin K has been identified. Starting from a potent inhibitor with poor oral bioavailability, modifications to P1 and P1' elements led to enhancements in solubility and permeability. These improvements resulted in orally available cathepsin K inhibitors. 相似文献
17.
Calpain-mediated proteolysis has been implicated as a major process in neuronal cell death including retinal neurological degeneration. The previously reported calpain inhibitor SJA6017 (1) showed oral efficacy in a retinal pharmacological model, but its oral bioavailability was low due to the metabolic lability and low water-solubility. The purpose of present study was to identify good orally bioavailable calpain inhibitors. A series of water-soluble dipeptidyl alpha-ketoamides containing a pyridine moiety at P3 were designed, synthesized, and evaluated for their oral bioavailability and retinal penetration. Introduction of a pyridineethanol moiety provided the potent alpha-ketoamide inhibitor 8 with good oral bioavailability. Compound 8 showed about 12-fold higher retinal AUC than 1. 相似文献
18.
Levin JI Chen JM Du MT Nelson FC Killar LM Skala S Sung A Jin G Cowling R Barone D March CJ Mohler KM Black RA Skotnicki JS 《Bioorganic & medicinal chemistry letters》2002,12(8):1199-1202
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing novel acetylenic P1' groups was explored. In particular, compound 4t bearing a butynyloxy P1' moiety has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and oral activity in an in vivo model of TNF-alpha production. 相似文献
19.
Barrett DG Catalano JG Deaton DN Long ST McFadyen RB Miller AB Miller LR Samano V Tavares FX Wells-Knecht KJ Wright LL Zhou HQ 《Bioorganic & medicinal chemistry letters》2007,17(1):22-27
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone. 相似文献
20.
Burgey CS Robinson KA Lyle TA Nantermet PG Selnick HG Isaacs RC Lewis SD Lucas BJ Krueger JA Singh R Miller-Stein C White RB Wong B Lyle EA Stranieri MT Cook JJ McMasters DR Pellicore JM Pal S Wallace AA Clayton FC Bohn D Welsh DC Lynch JJ Yan Y Chen Z Kuo L Gardell SJ Shafer JA Vacca JP 《Bioorganic & medicinal chemistry letters》2003,13(7):1353-1357