共查询到20条相似文献,搜索用时 15 毫秒
1.
Witherington J Blaney EL Bordas V Elliott RL Gaiba A Garton N Green PM Naylor A Smith DG Spalding DJ Takle AK Ward RW 《Bioorganic & medicinal chemistry letters》2006,16(21):5538-5541
A series of pyridone-N-benzyl-propanoic acids have been optimised to afford potent orally bioavailable VLA-4 antagonists. 相似文献
2.
Genicot C Christophe B Collart P Gillard M Goossens L Hénichart JP Lassoie MA Moureau F Neuwels M Nicolas JM Pasau P Quéré L Ryckmans T Stiernet F Taverne T Van Keulen BJ 《Bioorganic & medicinal chemistry letters》2003,13(3):437-442
Benzyloxyphenethylpiperazines are a new class of high affinity NK1 receptor antagonists. Oral bioavailability and selectivity can be fine tuned by the nature of the substituents on the basic nitrogen atom. Addition of substituents with a carboxylic acid group led to very selective and orally active NK1 antagonists free of interaction with L-type calcium channels. 相似文献
3.
Link JT Sorensen B Liu G Pei Z Reilly EB Leitza S Okasinski G 《Bioorganic & medicinal chemistry letters》2001,11(8):973-976
Diarylsulfide cyclopropylamides were synthesized and evaluated as LFA-1/ICAM-1 interaction antagonists. A substituent pattern was identified which maximized potency and minimized protein binding as exemplified by antagonist 30 (IC50 = 5 nM). 相似文献
4.
Gregori J. Morriello Sander G. Mills Tricia Johnson Mikhail Reibarkh Gary Chicchi Julie DeMartino Marc Kurtz P. Davies K.L.C. Tsao Song Zheng Xinchun Tong Emma Carlson Karen Townson F.D. Tattersall Alan Wheeldon Susan Boyce Neil Collinson Nadia Rupniak Stephen Moore Robert J. DeVita 《Bioorganic & medicinal chemistry letters》2010,20(6):2007-2012
Previous work on human NK1 (hNK1) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural–activity-relationship studies on simple α- and β-substituted compounds of this series provided several potent and bioavailable hNK1 antagonists that displayed excellent brain penetration as observed by their good efficacy in the gerbil foot-tapping (GFT) model assay. Several of these compounds exhibited 100% inhibition of the foot-tapping response at 0.1 and 24 h with ID50’s of less than 1 mpk. One particular α-substituted compound (2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity. 相似文献
5.
Xiao Ding Xuedong Dai Kai Long Cheng Peng Daniele Andreotti Paul Bamborough Andrew J. Eatherton Colin Edge Karamjit S. Jandu Paula L. Nichols Oliver J. Philps Luigi Piero Stasi Zehong Wan Jia-Ning Xiang Kelly Dong Pamela Dossang Ming-Hsun Ho Yi Li Feng Ren 《Bioorganic & medicinal chemistry letters》2017,27(17):4034-4038
Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson’s disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability. 相似文献
6.
Miller WH Manley PJ Cousins RD Erhard KF Heerding DA Kwon C Ross ST Samanen JM Takata DT Uzinskas IN Yuan CC Haltiwanger RC Gress CJ Lark MW Hwang SM James IE Rieman DJ Willette RN Yue TL Azzarano LM Salyers KL Smith BR Ward KW Johanson KO Huffman WF 《Bioorganic & medicinal chemistry letters》2003,13(8):1483-1486
In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123. 相似文献
7.
Kiyoi T Adam JM Clark JK Davies K Easson AM Edwards D Feilden H Fields R Francis S Jeremiah F McArthur D Morrison AJ Prosser A Ratcliffe PD Schulz J Wishart G Baker J Campbell R Cottney JE Deehan M Epemolu O Evans L 《Bioorganic & medicinal chemistry letters》2011,21(6):1748-1753
Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia. 相似文献
8.
《Bioorganic & medicinal chemistry letters》2020,30(17):127366
Antagonism of the Toll-like receptors (TLRs) 7 and TLR8 has been hypothesized to be beneficial to patients suffering from autoimmune conditions. A phenotypic screen for small molecule antagonists of TLR7/8 was carried out in a murine P4H1 cell line. Compound 1 was identified as a hit that showed antagonistic activity on TLR7 and TLR8 but not TLR9, as shown on human peripheral blood mononuclear cells (hPBMCs). It was functionally cross reactive with mouse TLR7 but lacked oral exposure and had only modest potency. Chemical optimization resulted in 2, which showed in vivo efficacy following intraperitoneal administration. Further optimization resulted in 8 which had excellent in vitro activity, exposure and in vivo activity. Additional work to improve physical properties resulted in 15, an advanced lead that had favorable in vitro and exposure properties. It was further demonstrated that activity of the series tracked with binding to the extracellular domain of TLR7 implicating that the target of this series are endosomal TLRs rather than downstream signaling pathways. 相似文献
9.
Chao J Taveras AG Chao J Aki C Dwyer M Yu Y Purakkattle B Rindgen D Jakway J Hipkin W Fosetta J Fan X Lundell D Fine J Minnicozzi M Phillips J Merritt JR 《Bioorganic & medicinal chemistry letters》2007,17(13):3778-3783
A novel series of cyclobutenedione centered C(4)-alkyl substituted furanyl analogs was developed as potent CXCR2 and CXCR1 antagonists. Compound 16 exhibits potent inhibitory activities against IL-8 binding to the receptors (CXCR2 Ki=1 nM, IC(50)=1.3 nM; CXCR1 Ki=3 nM, IC(50)=7.3 nM), and demonstrates potent inhibition against both Gro-alpha and IL-8 induced hPMN migration (chemotaxis: CXCR2 IC(50)=0.5 nM, CXCR1 IC(50)=37 nM). In addition, 16 has shown good oral pharmacokinetic profiles in rat, mouse, monkey, and dog. 相似文献
10.
Ueno H Yokota K Hoshi J Yasue K Hayashi M Uchida I Aisaka K Hase Y Katoh S Cho H 《Bioorganic & medicinal chemistry letters》2005,15(1):185-189
A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 (JTV-803) exhibited potent inhibitory activity against FXa and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkey, and showed a dose-dependent antithrombotic effect in a rat model of venous thrombosis. 相似文献
11.
Jin Q Nie H McCleland BW Widdowson KL Palovich MR Elliott JD Goodman RM Burman M Sarau HM Ward KW Nord M Orr BM Gorycki PD Busch-Petersen J 《Bioorganic & medicinal chemistry letters》2004,14(17):4375-4378
A series of 3-substituted N,N'-diarylureas was prepared and the structure-activity relationship relative to CXCR2 receptor affinity as well as their pharmacokinetic properties were examined. In vitro microsomal metabolism studies indicated that the lower clearance rates of the 3-sulfonamido-substituted compounds were most likely due to the suppression of glucuronidation. 相似文献
12.
《Bioorganic & medicinal chemistry》2019,27(20):114930
Phosphoinositide 3-kinases (PI3Ks) are regarded as promising targets for treatment of various cancers due to their roles in regulating cell proliferation, differentiation, migration, and survival. Here we report our efforts to develop potent and orally bioavailable PI3K inhibitors for the treatment of cancers. The alkylsulfonamide-containing quinazoline derivatives A1–A18 significantly inhibited PI3Kα, and cell proliferation among HCT-116, MCF-7 and SU-DHL-6 cell lines. The optimal compound A1 displayed potent inhibitory activity against PI3Kα (IC50 = 4.5 nM), PI3Kβ (IC50 = 4.5 nM), PI3Kγ (IC50 = 4.5 nM), PI3Kδ (IC50 = 4.5 nM) and significantly inhibited the growth of HCT-116, MCF-7 and SU-DHL-6 cell lines with IC50 values of 0.82 µM, 0.99 µM and 0.19 µM, respectively. Western blot analysis demonstrated A1 significantly suppressed the phosphorylation of AKTS473 in a dose-dependent manner. Furthermore, A1 could markedly inhibit cancer growth at the dose of 25 mg/kg in nude mouse HCT-116 xenograft model in vivo without causing significant weight loss or toxicity. 相似文献
13.
Berglund S Egner BJ Gradén H Gradén J Morgan DG Inghardt T Giordanetto F 《Bioorganic & medicinal chemistry letters》2008,18(17):4859-4863
A series of 1,3-disubstituted-1H-pyrrole-based antagonists of the human Melanin-Concentrating Hormone Receptor 1 (h-MCH-R1) are reported. High-throughput screening of the AstraZeneca compound collection yielded 1, a hit with moderate affinity towards MCH-R1. Subsequent structural manipulations and SAR analysis served to rationalize potency requirements, and 12 was identified as a novel, functional MCH-R1 antagonist with favorable pharmacokinetic properties. 相似文献
14.
Saravanan Parthasarathy Kenneth Henry Huaxing Pei Josh Clayton Mark Rempala Deidre Johns Oscar De Frutos Pablo Garcia Carlos Mateos Sehila Pleite Yong Wang Stephanie Stout Bradley Condon Sheela Ashok Zhohai Lu William Ehlhardt Tom Raub Mei Lai Timothy P. Burkholder 《Bioorganic & medicinal chemistry letters》2018,28(10):1887-1891
During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model. 相似文献
15.
Lin LS Kopka IE Mumford RA Magriotis PA Lanza T Durette PL Kamenecka T Young DN de Laszlo SE McCauley E Riper GV Kidambi U Egger LA Tong X Lyons K Vincent S Stearns R Colletti A Teffera Y Fenyk-Melody J Schmidt JA MacCoss M Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(4):611-614
Acylated beta-amino acids are described as potent, specific and orally bioavailable antagonists of VLA-4. The initial lead was identified from a combinatorial library. Subsequent optimization using a traditional medicinal chemistry approach led to significant improvement in potency (up to 8-fold) while maintaining good pharmacokinetic properties. 相似文献
16.
《Bioorganic & medicinal chemistry letters》2019,29(20):126668
Type 2 diabetes mellitus (T2DM) is characterized by chronically elevated plasma glucose levels. The inhibition of glucagon-induced hepatic glucose output via antagonism of the glucagon receptor (GCGR) using a small-molecule antagonist is a promising mechanism for improving glycemic control in the diabetic state. The present work discloses the discovery of indazole-based β-alanine derivatives as potent GCGR antagonists through an efficient enantioselective synthesis and structure-activity relationship (SAR) exploration and optimization. Compounds within this class exhibited excellent pharmacokinetic properties in multiple preclinical species. In an acute dog glucagon challenge test, compound 13K significantly inhibited glucagon-mediated blood glucose increase when dosed orally at 10 mg/kg. 相似文献
17.
Patel D Jain M Shah SR Bahekar R Jadav P Joharapurkar A Dhanesha N Shaikh M Sairam KV Kapadnis P 《Bioorganic & medicinal chemistry letters》2012,22(2):1111-1117
A novel series of pTyr mimetics containing triaryl-sulfonamide derivatives (5a-r) are reported as potent and selective PTP1B inhibitors. Some of the test compounds (5o and 5p) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro). The lead compound 5o showed potent antidiabetic activity (in vivo), along with improved pharmacokinetic profile. These preliminary results confirm discovery of highly potent and selective PTP1B inhibitors for the treatment of T2DM. 相似文献
18.
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
19.
Wang GT Wang S Gentles R Sowin T Leitza S Reilly EB von Geldern TW 《Bioorganic & medicinal chemistry letters》2005,15(1):195-201
2-Amino-4-phenyl pyridine and, to a lesser extent, 4-amino-6-phenyl pyrimidine, were established as isosteres of trans-cinnamide moiety. Applying this isosterism to previously reported p-arylthio cinnamides resulted in the identification of 4-amino-6-(p-arylthio)phenyl-pyrimidines and 2-amino-4-(p-arylthio)phenyl-pyridines as potent antagonists of LFA-1/ICAM-1 binding. 相似文献
20.
Haga Y Mizutani S Naya A Kishino H Iwaasa H Ito M Ito J Moriya M Sato N Takenaga N Ishihara A Tokita S Kanatani A Ohtake N 《Bioorganic & medicinal chemistry》2011,19(2):883-893
The design, synthesis and structure-activity relationships of a novel class of N-phenylpyridone MCH1R antagonists are described. The core part of the N-phenylpyridone structure was newly designed and the side chain moieties that were attached to the core part were extensively explored. As a result of optimization of the N-phenylpyridone leads, we successfully developed the orally available, and brain-penetrable MCH1R selective antagonist 7c, exhibiting excellent anti-obese effect in diet-induced obese (DIO) mice. 相似文献