共查询到20条相似文献,搜索用时 28 毫秒
1.
Susanne Berglund Bryan J. Egner Henrik Gradén Joakim Gradén David G.A. Morgan Tord Inghardt Fabrizio Giordanetto 《Bioorganic & medicinal chemistry letters》2009,19(15):4268-4273
Herein, we disclose the discovery and optimization of 2-piperidin-4-yl-acetamide derivatives as MCH-R1 antagonists. Structural investigation of piperidin-4-yl-amide and piperidin-4-yl-ureas identified 2-piperidin-4-yl-acetamide-based MCH-R1 antagonists with outstanding in vivo efficacy but flawed with high affinity towards the hERG potassium channel. While existing hERG SAR information was employed to discover highly potent MCH-R1 antagonists with minimized hERG inhibition, additional hurdles prevented their subsequent clinical exploration. 相似文献
2.
Chae Jo Lim Ji Young Kim Byung Ho Lee Kwang-Seok Oh Kyu Yang Yi 《Bioorganic & medicinal chemistry letters》2013,23(6):1736-1739
The discovery and optimization of novel pyrrolo[3,4-b]pyridin-7(6H)-one MCH-R1 antagonists are described. A systematic SAR study probing the effects of aryl-, benzyl- and arylthio-substituents at the 2-position of the pyrrolo[3,4-b]pyridin-7(6H)-ones led to identification of the 2-[(4-fluorophenyl)thio] derivative 7b as a highly potent MCH-R1 antagonist. This compound also has favorable pharmacokinetic properties along with a high metabolic stability and a minimal impact on CYP isoforms and hERG. 相似文献
3.
Meyers KM Méndez-Andino JL Colson AO Warshakoon NC Wos JA Mitchell MC Hodge KM Howard JM Ackley DC Holbert JK Mittelstadt SW Dowty ME Obringer CM Reizes O Hu XE 《Bioorganic & medicinal chemistry letters》2007,17(3):819-822
A direct correlation between hERG binding and QTc prolongation was established for a series of aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists. Compounds within this class with greater selectivity over hERG were developed. Compound 4h proved to have the best profile, with MCH-R1 Ki = 16 nm and hERG IC50 = 25 microM. 相似文献
4.
Lim CJ Kim N Lee EK Lee BH Oh KS Yoo SE Yi KY 《Bioorganic & medicinal chemistry letters》2011,21(8):2309-2312
Compounds containing 2-arybenzimidazole ring systems linked to arylpiperidines were synthesized and evaluated as MCH-R1 antagonists. The results of structure-activity relationship studies led to the identification of compound 4c as a potent MCH-R1 antagonist (IC50 = 1 nM). This compound also has good metabolic stability, and favorable pharmacokinetic and brain penetration properties. However 4c was found to be potent inhibitor of the hERG potassium channel. 相似文献
5.
Meyers KM Kim N Méndez-Andino JL Hu XE Mumin RN Klopfenstein SR Wos JA Mitchell MC Paris JL Ackley DC Holbert JK Mittelstadt SW Reizes O 《Bioorganic & medicinal chemistry letters》2007,17(3):814-818
Aminomethyl tetrahydronaphthalene biphenyl carboxamide MCH-R1 antagonists with greater selectivity over hERG were identified. SAR studies addressing two distinct alternatives for structural modifications leading to improve hERG selectivity are described. 相似文献
6.
A novel series of 4-arylphthalazin-1(2H)-one linked to arylpiperidines were synthesized and evaluated as MCH-R1 antagonists. The results of an extensive SAR study probing the effects of substituents on the 4-arylphthalazin-1(2H)-one C-4 aryl group led to the identification of the 4-(3,4-difluorophenyl) derivative as a highly potent MCH-R1 inhibitor with an IC(50)=1nM. However, further investigations showed that this substance has unacceptable pharmacokinetic properties including a high clearance and volume of distribution. 相似文献
7.
Giordanetto F Karlsson O Lindberg J Larsson LO Linusson A Evertsson E Morgan DG Inghardt T 《Bioorganic & medicinal chemistry letters》2007,17(15):4232-4241
We herein report the optimization of cyclopentane- and cyclohexane-1,3-diamine derivatives as novel and potent MCH-R1 antagonists. Structural modifications of the 2-amino-quinoline and thiophene moieties found in the initial lead compound served to improve its metabolic stability profile and MCH-R1 affinity, and revealed unprecedented SAR when compared to other 2-amino-quinoline-containing MCH-R1 antagonists. 相似文献
8.
Méndez-Andino JL Colson AO Meyers KM Mitchell MC Hodge K Howard JM Kim N Ackley DC Holbert JK Mittelstadt SW Dowty ME Obringer CM Suchanek P Reizes O Hu XE Wos JA 《Bioorganic & medicinal chemistry》2007,15(5):2092-2105
The design, synthesis, and biological studies of a novel class of MCH-R1 antagonists based on an aminotetrahydronaphthalene ketopiperazine scaffold is described. Compounds within this class promoted significant body weight reduction in mouse diet induced obesity studies. The potential for hERG blockage activity and QT interval studies in anesthetized dogs are discussed. 相似文献
9.
Mohamed A. Helal Amar G. Chittiboyina Mitchell A. Avery 《Bioorganic & medicinal chemistry letters》2019,29(24):126741
MCH receptor is a G protein-coupled receptor with two subtypes R1 and R2. Many studies have demonstrated the role of MCH-R1 in feeding and energy homeostasis. It has been proven that oral administration of small molecule MCH-R1 antagonists significantly reduces food intake and causes a dose-dependent weight loss. In this study, two ligand-based pharmacophores were developed and validated based on recently published MCH-R1 antagonists with diverse structures. Successful pharmacophores had one hydrogen bond acceptor, one positive ionizable, one ring aromatic and two or three hydrophobic groups. These 3D-QSAR models were used for virtual screening of the ZINC chemical database resulting in the identification of nine compounds with more than 50% displacement of radiolabeled MCH at a 20 μM concentration. Moreover, four of these compounds showed antagonistic activities in Aequorin functional assay, including MH-3 which is the first MCH-R1 antagonist based on a diazaspiro[4.5]decane scaffold. The most active compounds were also docked into our previously published MCH-R1 homology model to gain insights into their binding determinants. These compounds could represent a viable starting scaffold for the design of potent MCH-R1 antagonists with improved pharmacokinetic properties as an effective treatment for obesity. 相似文献
10.
Zhang X Hufnagel H Markotan T Lanter J Cai C Hou C Singer M Opas E McKenney S Crysler C Johnson D Sui Z 《Bioorganic & medicinal chemistry letters》2011,21(18):5577-5582
A series of 4-azetidinyl-1-aryl-cyclohexanes as potent CCR2 antagonists with high selectivity over activity for the hERG potassium channel is discovered through divergent SARs of CCR2 and hERG. 相似文献
11.
Huang CQ Baker T Schwarz D Fan J Heise CE Zhang M Goodfellow VS Markison S Gogas KR Chen T Wang XC Zhu YF 《Bioorganic & medicinal chemistry letters》2005,15(16):3701-3706
Derivatives of 1-(4-amino-phenyl)-pyrrolidin-3-yl-amine and 6-(3-amino-pyrrolidin-1-yl)-pyridin-3-yl-amine were identified as potent and functionally active MCH-R1 antagonists. One compound with Ki = 2.3 nM demonstrated good oral bioavailability (32%) and in vivo efficacy in rats. 相似文献
12.
Meyers KM Méndez-Andino J Colson AO Hu XE Wos JA Mitchell MC Hodge K Howard J Paris JL Dowty ME Obringer CM Reizes O 《Bioorganic & medicinal chemistry letters》2007,17(3):657-661
The synthesis and biological testing of novel classes of potent melanin-concentrating hormone (MCH-R1) antagonists based on pyrazolopiperazinone and pyrrolopiperazinone scaffolds are described. 相似文献
13.
Ma V Bannon AW Baumgartner J Hale C Hsieh F Hulme C Rorrer K Salon J van Staden C Tempest P 《Bioorganic & medicinal chemistry letters》2006,16(19):5066-5072
Melanin-concentrating hormone (MCH) is a cyclic 19 amino acid orexigenic neuropeptide. The action of MCH on feeding is thought to involve the activation of its respective G protein-coupled receptor MCH-R1. Consequently, antagonists that block MCH regulated MCH-R1 activity may provide a viable approach to the treatment of diet-induced obesity. This communication reports the discovery of a novel MCH-R1 receptor antagonist, the biarylether 7, identified through high throughput screening. The solid-phase synthesis and structure-activity relationship of related analogs is described. 相似文献
14.
Chae Jo Lim Nam Hui Kim Hye Jin Park Byung Ho Lee Kwang-Seok Oh Kyu Yang Yi 《Bioorganic & medicinal chemistry letters》2019,29(4):577-580
The synthesis and biological evaluation as potential urotensin-II receptor antagonists of a series of 5-arylfuran-2-carboxamide derivatives 1, bearing a 4-(3-chloro-4-(piperidin-4-yloxy)benzyl)piperazin-1-yl group, are described. The results of a systematic SAR investigation of furan-2-carboxamides with C-5 aryl groups possessing a variety of aryl ring substituents led to identification of the 3,4-difluorophenyl analog 1y as a highly potent UT antagonist with an IC50 value of 6?nM. In addition, this substance was found to display high metabolic stability, and low hERG inhibition and cytotoxicity, and to have an acceptable PK profile. 相似文献
15.
Kanuma K Omodera K Nishiguchi M Funakoshi T Chaki S Nagase Y Iida I Yamaguchi J Semple G Tran TA Sekiguchi Y 《Bioorganic & medicinal chemistry》2006,14(10):3307-3319
The optimization of the distance between two key pharmacophore features within our first hit compounds 1a and 2a led to the identification of a new class of potent non-peptidic antagonists for the MCH-R1, based around 4-amino-2-cyclohexylaminoquinazolines. In particular, ATC0065 (2c), N2-[cis-4-([2-[4-Bromo-2-(trifluoromethoxy)phenyl]ethyl]amino)cyclohexyl]-N4,N4-dimethylquinazoline-2,4-diamine dihydrochloride, bound with high affinity to the MCH-R1 (IC50 value of 16 nM) and showed good metabolic stability in liver microsomes from human and rat. 相似文献
16.
Méndez-Andino J Colson AO Denton D Mitchell MC Cross-Doersen D Hu XE 《Bioorganic & medicinal chemistry letters》2007,17(3):832-835
We have identified a novel series of potent MCH-R1 antagonists based on l-arginine. As predicted by computational methods, there was an activity dependence on the pi-electronic character of the aromatic systems corresponding to the amino-terminus of these molecules. These results have enhanced our understanding of the MCH-R1 receptor and the potential for a predictive homology model. 相似文献
17.
Zhang X Hufnagel H Hou C Opas E McKenney S Crysler C O'Neill J Johnson D Sui Z 《Bioorganic & medicinal chemistry letters》2011,21(20):6042-6048
A novel series of 4-azetidinyl-1-aryl-cyclohexanes containing indazole or benzoisoxazole moiety have been identified as potent CCR2 antagonists with high selectivity versus hERG. 相似文献
18.
Judd AS Souers AJ Wodka D Zhao G Mulhern MM Iyengar RR Gao J Lynch JK Freeman JC Falls HD Brodjian S Dayton BD Reilly RM Gintant G Limberis JT Mikhail A Leitza ST Houseman KA Diaz G Bush EN Shapiro R Knourek-Segel V Hernandez LE Marsh KC Sham HL Collins CA Kym PR 《Bioorganic & medicinal chemistry letters》2007,17(8):2365-2371
A series of potent 2-carboxychromone-based melanin-concentrating hormone receptor 1 (MCHr1) antagonists were synthesized and evaluated for hERG (human Ether-a-go-go Related Gene) channel affinity and functional blockade. Basic dialkylamine-terminated analogs were found to weakly bind the hERG channel and provided marked improvement in a functional patch-clamp assay versus previously reported antagonists of the series. 相似文献
19.
Hudkins RL Zulli AL Dandu Rr Tao M Josef KA Aimone LD Haltiwanger RC Huang Z Lyons JA Mathiasen JR Raddatz R Gruner JA 《Bioorganic & medicinal chemistry letters》2012,22(4):1504-1509
Structure-activity relationships for a series of phenoxypiperidine pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. The search for compounds with improved hERG and DAT selectivity without the formation of in vivo active metabolites identified 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one 17b. Compound 17b met discovery flow criteria, demonstrated potent H(3)R functional antagonism in vivo in the rat dipsogenia model and potent wake activity in the rat EEG/EMG model at doses as low as 0.1 mg/kg ip. 相似文献
20.
Palani A Shapiro S McBriar MD Clader JW Greenlee WJ O'Neill K Hawes B 《Bioorganic & medicinal chemistry letters》2005,15(23):5234-5236
Herein, we report the discovery of the potent and selective biaryl diamide derived MCH-R1 receptor antagonist 1, which was identified upon modification of a previously disclosed biaryl urea series. This paper describes one of the strategies incorporated to remove the highly mutagenic biarylaniline present in an otherwise promising biaryl urea series. 相似文献