共查询到20条相似文献,搜索用时 15 毫秒
1.
Synthesis and structure-activity relationships of novel poly(ADP-ribose) polymerase-1 inhibitors 总被引:1,自引:0,他引:1
Tao M Park CH Bihovsky R Wells GJ Husten J Ator MA Hudkins RL 《Bioorganic & medicinal chemistry letters》2006,16(4):938-942
A series of novel pyrrolocarbazoles was synthesized as potential PARP-1 inhibitors. Pyrrolocarbazole 1 was identified as a potent PARP-1 inhibitor (IC50 = 36 nM) from our internal database. Synthesis of analogs around this template with the aid of modeling studies led to the identification of the truncated imide 14. Compound 14 (IC50 = 40 nM), with deleted B-ring, was found to be an equipotent PARP-1 inhibitor. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2014,24(12):2669-2673
The isoquinolinone-based tricyclic compounds were designed and synthesized. Preliminary biological study of these compounds provided potent compounds 17a, 33b, 33c, 33d, and 33g with low nanomolar IC50s against PARP-1 enzyme. 相似文献
3.
Substituted uracil derivatives as potent inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1) 总被引:1,自引:0,他引:1
Steinhagen H Gerisch M Mittendorf J Schlemmer KH Albrecht B 《Bioorganic & medicinal chemistry letters》2002,12(21):3187-3190
A new class of PARP-1 inhibitors, namely substituted fused uracil derivatives were synthesised. Starting from a derivative with an IC(50)=2microM the chemical optimisation program led to compounds with more than a 100-fold increase in potency (IC(50)<20nM). Additionally, physicochemical and pharmacokinetic properties were evaluated. It could be shown that compounds bearing a piperazine or phenyl substituted betaAla-Gly side chain exhibited the best overall profile. 相似文献
4.
Hee-Kyung Rhee So Yun Lim Mi-Ja Jung Youngjoo Kwon Myung-Hwa Kim Hea-Young Park Choo 《Bioorganic & medicinal chemistry》2009,17(21):7537-7541
The isoquinolinone-based tetracyclic compounds were designed and synthesized and their PARP-1 inhibitory activity was evaluated. Most of synthesized compounds showed fairly good activity. Also the most active compound 6 showed its activity on potentiation of anticancer agents, temozolamide and etoposide, by 1.7 times, respectively. 相似文献
5.
Julie Miyashiro Keith W. Woods Chang H. Park Xuesong Liu Yan Shi Eric F. Johnson Jennifer J. Bouska Amanda M. Olson Yan Luo Elizabeth H. Fry Vincent L. Giranda Thomas D. Penning 《Bioorganic & medicinal chemistry letters》2009,19(15):4050-4054
Based on screening hit 1, a series of tricyclic quinoxalinones have been designed and evaluated for inhibition of PARP-1. Substitutions at the 7- and 8-positions of the quinoxalinone ring led to a number of compounds with good enzymatic and cellular potency. The tricyclic quinoxalinone class is sensitive to modifications of both the amine substituent and the tricyclic core. The synthesis and structure–activity relationship studies are presented. 相似文献
6.
Caterina Torrisi Monica Bisbocci Raffaele Ingenito Jesus M. Ontoria Michael Rowley Carsten Schultz-Fademrecht Carlo Toniatti Philip Jones 《Bioorganic & medicinal chemistry letters》2010,20(2):448-452
A novel hexahydrobenzonaphthyridinone PARP-1 pharmacophore is reported, subsequent SAR exploration around this scaffold led to selective PARP-1 inhibitors with low nanomolar enzyme potency, displaying good cellular activity and promising rat PK properties. 相似文献
7.
Chun-Ho Park Kwangwoo Chun Bo-Young Joe Ji-Seon Park Young-Chul Kim Ji-Soo Choi Dong-Kyu Ryu Seong-Ho Koh Goang Won Cho Seung Hyun Kim Myung-Hwa Kim 《Bioorganic & medicinal chemistry letters》2010,20(7):2250-2253
Highly potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors, including 9-hydroxy-1,2-dihydro-4H-thiopyrano[3,4-c]quinolin-5(6H)-one derivatives with a non-aromatic A-ring, were synthesized. Among the derivatives, 12a showed low nanomolar enzyme and cellular activity (IC50 = 42 nM, ED50 = 220 nM) with good water solubility. Further, 12a exhibited microsomal stability in vitro and brain permeability in vivo. 相似文献
8.
Synthesis and activity of a series of 3-aroyl-derived analogs of novel pyrrolocarbazole 1 as poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors are disclosed. 相似文献
9.
Synthesis and activity of a series of 4-thiazol-yl substituted analogs of novel pyrrolocarbazole 1 as poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been disclosed. 相似文献
10.
Ferraris D Ficco RP Dain D Ginski M Lautar S Lee-Wisdom K Liang S Lin Q Lu MX Morgan L Thomas B Williams LR Zhang J Zhou Y Kalish VJ 《Bioorganic & medicinal chemistry》2003,11(17):3695-3707
A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC(50)=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia. 相似文献
11.
Danila Branca Mauro Cerretani Philip Jones Uwe Koch Federica Orvieto Maria Cecilia Palumbi Michael Rowley Carlo Toniatti Ester Muraglia 《Bioorganic & medicinal chemistry letters》2009,19(15):4042-4045
PARP inhibitors have been demonstrated to retard intracellular DNA repair and therefore sensitize tumor cells to cytotoxic agents or ionizing radiation. We report the identification of a novel class of PARP1 inhibitors, containing a pyrrolo moiety fused to a dihydroisoquinolinone, derived from virtual screening of the proprietary collection. SAR exploration around the nitrogen of the aminoethyl appendage chain of 1 led to compounds that displayed low nanomolar activity in a PARP1 enzymatic assay. 相似文献
12.
Jagtap PG Southan GJ Baloglu E Ram S Mabley JG Marton A Salzman A Szabó C 《Bioorganic & medicinal chemistry letters》2004,14(1):81-85
A series of novel 4-(N-acyl)-2,3-dihydro-1H-isoindol-1-ones have been prepared from methyl-3-nitro-2-methylbenzoate and linked through various spacers to the adenosine derivatives 11 and 12. We found that potent inhibition of poly(ADP-ribose)polymerase-1 (PARP-1) was achieved when isoindolinone was linked to adenosine by a spacer group of a specific length. Introduction of piperazine and succinyl linkers between the isoindolinone and adenosine core structures resulted in highly potent compounds 8a and 10b, which showed IC(50) values of 45 and 100 nM, respectively. 相似文献
13.
Federica Orvieto Danila Branca Claudia Giomini Philip Jones Uwe Koch Jesus M. Ontoria Maria Cecilia Palumbi Michael Rowley Carlo Toniatti Ester Muraglia 《Bioorganic & medicinal chemistry letters》2009,19(15):4196-4200
A novel series of pyrazolo[1,5-a]quinazolin-5(4H)-one derivatives proved to be a potent class of PARP-1 inhibitors. An extensive SAR around the 3-position of pyrazole in the scaffold led to the discovery of amides derivatives as low nanomolar PARP-1 inhibitors. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2001,11(13):1687-1690
1-, 2-, 3-, 4-, 8-, or 10-Substituted 5(H)phenanthridin-6-ones were synthesized and found to be potent PARP1 inhibitors. Among the 28 compounds prepared, some showed not only low IC50 values (compound 1b, 10 nM) but also desirable water solubility characteristics. These properties, which are superior to the common PARP1 inhibitors such as benzamides and isoquinolin-1-ones, are essential for potential therapeutic usage. The variety of compounds allows SAR analysis of favored substituents and substituted positions on 5(H)phenanthridin-6-one ring. 相似文献
15.
16.
Moree WJ Goldman P Demaggio AJ Christenson E Herendeen D Eksterowicz J Kesicki EA McElligott DL Beaton G 《Bioorganic & medicinal chemistry letters》2008,18(18):5126-5129
A novel class of PARP-1 inhibitors was identified containing a non-aromatic heterocycle or carbocycle fused to a pyrazolo pyridin-2-one. Compounds displayed low nanomolar binding activity in the PARP-1 binding assay and submicromolar activity in a cell based chemosensitization assay. 相似文献
17.
Discovery of quinazolinone and quinoxaline derivatives as potent and selective poly(ADP-ribose) polymerase-1/2 inhibitors 总被引:2,自引:0,他引:2
Iwashita A Hattori K Yamamoto H Ishida J Kido Y Kamijo K Murano K Miyake H Kinoshita T Warizaya M Ohkubo M Matsuoka N Mutoh S 《FEBS letters》2005,579(6):1389-1393
Two classes of quinazolinone derivatives and quinoxaline derivatives were identified as potent and selective poly(ADP-ribose) polymerase-1 and 2 (PARP-1) and (PARP-2) inhibitors, respectively. In PARP enzyme assays using recombinant PARP-1 and PARP-2, quinazolinone derivatives displayed relatively high selectivity for PARP-1 and quinoxaline derivatives showed superior selectivity for PARP-2. SBDD analysis via a combination of X-ray structural study and homology modeling suggested distinct interactions of inhibitors with PARP-1 and PARP-2. These findings provide a new structural framework for the design of selective inhibitors for PARP-1 and PARP-2. 相似文献
18.
Giovanna Pescatore Danila Branca Fabrizio Fiore Olaf Kinzel Laura Llauger Bufi Ester Muraglia Federica Orvieto Michael Rowley Carlo Toniatti Caterina Torrisi Philip Jones 《Bioorganic & medicinal chemistry letters》2010,20(3):1094-1099
Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells. 相似文献
19.
《Bioorganic & medicinal chemistry》2014,22(5):1700-1707
Imaging of poly (ADP-ribose) polymerase-1 (PARP-1) expression in vivo is a potentially powerful tool for developing PARP-1 inhibitors for drug discovery and patient care. We have synthesized several derivatives of benzimidazole carboxamide as PARP-1 inhibitors, which can be 18F-labeled easily for positron emission tomographic (PET) imaging. Of the compounds synthesized, 12 had the highest inhibition potency for PARP-1 (IC50 = 6.3 nM). [18F]12 was synthesized under conventional conditions in high specific activity with 40–50% decay-corrected yield. MicroPET studies using [18F]12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [18F]12 in the tumor that was blocked by olaparib, suggesting that the uptake of [18F]12 in the tumor is specific to PARP-1 expression. 相似文献
20.
A simple and versatile method for preparation of (D)-Phe-Pro peptidomimetic bicyclic thiazolidine lactams is presented. These bicyclic lactams have chemical diversity alpha to the lactam carbonyl and, when linked to electrophilic arginines, provide potent thrombin inhibitors. 相似文献