共查询到20条相似文献,搜索用时 15 毫秒
1.
《Bioorganic & medicinal chemistry》2016,24(16):3494-3500
The neurokinin B (NKB)–neurokinin-3 receptor (NK3R) signaling positively regulates the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. The NK3R-selective antagonists may suppress the reproductive functions of mammals. For development of novel NK3R antagonists with reduced environmental toxicity, a structure–activity relationship study of an NK3R antagonist, talnetant, was carried out. Among several talnetant derivatives with labile functional groups in the natural environment, 3-mercaptoquinoline 2f exhibited a comparable biological activity to that of the parent talnetant. Additionally, compound 2f was converted into the disulfide 3f or isothiazolone 8 by air-oxidation, both of which showed no binding affinity to NK3R. 相似文献
2.
Chackalamannil S Doller D Eagen K Czarniecki M Ahn HS Foster CJ Boykow G 《Bioorganic & medicinal chemistry letters》2001,11(21):2851-2853
Several benzimidazole derivatives have been identified as potent thrombin receptor (PAR-1) antagonists as represented by compound 1h, which showed an IC(50) of 33 nM. 相似文献
3.
Davies DJ Crowe M Lucas N Quinn J Miller DD Pritchard S Grose D Bettini E Calcinaghi N Virginio C Abberley L Goldsmith P Michel AD Chessell IP Kew JN Miller ND Gunthorpe MJ 《Bioorganic & medicinal chemistry letters》2012,22(7):2620-2623
A series of novel benzimidazoles are discussed as NR2B-selective N-methyl-d-aspartate (NMDA) receptor antagonists. High throughput screening (HTS) efforts identified a number of potent and selective NR2B antagonists such as 1. Exploration of the substituents around the core of this template identified a number of compounds with high potency for NR2B (pIC(50) >7) and good selectivity against the NR2A subunit (pIC(50) <4.3) as defined by FLIPR-Ca(2+) and radioligand binding studies. These agents offer potential for the development of therapeutics for a range of nervous system disorders including chronic pain, neurodegeneration, migraine and major depression. 相似文献
4.
Kurukulasuriya R Sorensen BK Link JT Patel JR Jae HS Winn MX Rohde JR Grihalde ND Lin CW Ogiela CA Adler AL Collins CA 《Bioorganic & medicinal chemistry letters》2004,14(9):2047-2050
Biaryl amides derived from a reported series of ureas 1 were evaluated and found to be potent human glucagon receptor antagonists. The benzofuran analogue 6i was administered in Sprague-Dawley rats and blocked the effects of an exogenous glucagon challenge. 相似文献
5.
Shuangjie Shu Antao Dai Jiang Wang Bin Wang Yang Feng Jia Li Xiaoqing Cai Dehua Yang Dakota Ma Ming-Wei Wang Hong Liu 《Bioorganic & medicinal chemistry》2018,26(8):1896-1908
A novel series of 4-methyl substituted pyrazole derivatives were designed, synthesized and biologically evaluated as potent glucagon receptor (GCGR) antagonists. In this study, compounds 9q, 9r, 19d and 19e showed high GCGR binding (IC50?=?0.09?μM, 0.06?μM, 0.07?μM and 0.08?μM, respectively) and cyclic-adenosine monophosphate (cAMP) activities (IC50?=?0.22?μM, 0.26?μM, 0.44?μM and 0.46?μM, respectively) in cell-based assays. Most importantly, the docking experiment demonstrated that compound 9r formed extensive hydrophobic interactions with the receptor binding pocket, making it justifiable to further investigate the potential of becoming a GCGR antagonist. 相似文献
6.
Hojung Choi Chang-Yong Lee Eun-Young Park Kyoung Mee Lee Dongyun Shin Hee-Sook Jun 《Bioorganic & medicinal chemistry》2018,26(21):5701-5710
The hormone glucagon increases blood glucose levels through increasing hepatic glucose output. In diabetic patients, dysregulation of glucagon secretion contributes to hyperglycemia. Thus, the inhibition of glucagon receptor is one target for the treatment of hyperglycemia in type 2 diabetes. Here we designed and synthesized a series of small molecules based on phenylpyrimidine. Of these, the compound (R)-7a most significantly decreased the glucagon-induced cAMP production and glucagon-induced glucose production during in vitro and in vivo assays. In addition, (R)-7a showed good efficacy in glucagon challenge tests and lowered blood glucose levels in diabetic db/db mice. Our results suggest that the compound (R)-7a could be a potential glucose-lowering agent for treating type 2 diabetes. 相似文献
7.
Discovery of novel, potent, and orally active spiro-urea human glucagon receptor antagonists 总被引:4,自引:0,他引:4
Shen DM Zhang F Brady EJ Candelore MR Dallas-Yang Q Ding VD Dragovic J Feeney WP Jiang G McCann PE Mock S Qureshi SA Saperstein R Shen X Tamvakopoulos C Tong X Tota LM Wright MJ Yang X Zheng S Chapman KT Zhang BB Tata JR Parmee ER 《Bioorganic & medicinal chemistry letters》2005,15(20):4564-4569
A novel class of spiro-ureas has been discovered as potent human glucagon receptor antagonists in both binding and functional assays. Preliminary studies have revealed that compound 15 is an orally active human glucagon receptor antagonist in a transgenic murine pharmacodynamic model at 10 and 30 mpk. Compound 15 is orally bioavailable in several preclinical species and shows selectivity toward cardiac ion channels and other family B receptors, such as hGIP1 and hGLP. 相似文献
8.
Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor 总被引:1,自引:0,他引:1
Duffy JL Kirk BA Konteatis Z Campbell EL Liang R Brady EJ Candelore MR Ding VD Jiang G Liu F Qureshi SA Saperstein R Szalkowski D Tong S Tota LM Xie D Yang X Zafian P Zheng S Chapman KT Zhang BB Tata JR 《Bioorganic & medicinal chemistry letters》2005,15(5):1401-1405
A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. Systematic modification of the lead compound identified substituents that were essential for activity and those that were amenable to further optimization. This SAR exploration resulted in the synthesis of 13, which exhibited good potency as an hGCGR functional antagonist (IC50 = 34 nM) and moderate bioavailability (36% in mice). 相似文献
9.
L L Chang K L Sidler M A Cascieri S de Laszlo G Koch B Li M MacCoss N Mantlo S O'Keefe M Pang A Rolando W K Hagmann 《Bioorganic & medicinal chemistry letters》2001,11(18):2549-2553
A modestly active, nonselective triarylimidazole lead was optimized for binding affinity with the human glucagon receptor. This led to the identification of a 2- and/or 4-alkyl or alkyloxy substituent on the imidazole C4-aryl group as a structural determinant for significant enhancement in binding with the glucagon receptor (e.g., 41, IC(50)=0.053 microM) and selectivity (>1000x) over p38MAP kinase in this class of compounds. 相似文献
10.
de Laszlo SE Hacker C Li B Kim D MacCoss M Mantlo N Pivnichny JV Colwell L Koch GE Cascieri MA Hagmann WK 《Bioorganic & medicinal chemistry letters》1999,9(5):641-646
The SAR of 2-pyridyl-3,5-diaryl pyrroles, ligands of the human glucagon receptor and inhibitors of p38 kinase, were investigated. This effort resulted in the identification of 2-(4-pyridyl)-5-(4-chlorophenyl)-3-(5-bromo-2-propyloxyphenyl)pyrr ole 49 (L-168,049), a potent (Kb = 25 nM), selective antagonist of glucagon. 相似文献
11.
Chebib M Johnston GA Mattsson JP Rydström K Nilsson K Qiu J Stevenson SH Silverman RB 《Bioorganic & medicinal chemistry letters》1999,9(21):3093-3098
3- and 4-(Aminomethyl)-2,6-difuorophenols were tested for activity against the three major classes of GABA receptors. 4-(Amninomethyl)-2,6difluorophenol was shown to be a competitive and somewhat selective antagonist at p1 GABA(C) receptors expressed in Xenopus oocytes (K(B) = 75.5 microM with a 95% Confidence Interval range of 75.2 microM to 75.8 microM). This is the first in a novel class of increased lipophilicity GABA(C) receptor antagonists with little activity at alpha1beta2gamma2 GABA(A) and GABA(B) receptors. 相似文献
12.
《Bioorganic & medicinal chemistry》2016,24(4):789-801
Several androgen receptor (AR) antagonists are clinically prescribed to treat prostate cancer. Unfortunately, many patients become resistant to the existing AR antagonists. To overcome this, a novel AR antagonist candidate called DIMN was discovered by our research group in 2013. In order to develop compounds with improved potency, we designed novel DIMN derivatives based on a docking study and substituted carbons with heteroatom moieties. Encouraging in vitro results for compounds 1b, 1c, 1e, 3c, and 4c proved that the new design was successful. Among the newly synthesized compounds, 1e exhibited the strongest inhibitory effect on LNCaP cell growth (IC50 = 0.35 μM) and also acted as a competitive AR antagonist with selectivity over the estrogen receptor (ER) and the glucocorticoid receptor (GR). A docking study of compound 1e fully supported these biological results. Compound 1e is considered to be a novel, potent and AR-specific antagonist for treating prostate cancer. Thus, our study successfully applied molecular modeling and bioisosteric replacement for hit optimization. The methods here provide a guide for future development of drug candidates through structure-based drug discovery and chemical modifications. 相似文献
13.
Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity 总被引:1,自引:0,他引:1
Lange JH van Stuivenberg HH Veerman W Wals HC Stork B Coolen HK McCreary AC Adolfs TJ Kruse CG 《Bioorganic & medicinal chemistry letters》2005,15(21):4794-4798
Novel 3,4-diarylpyrazolines 1 as potent CB1 receptor antagonists with lipophilicity lower than that of SLV319 are described. The key change is the replacement of the arylsulfonyl group in the original series by a dialkylaminosulfonyl moiety. The absolute configuration (4S) of eutomer 24 was established by X-ray diffraction analysis and 24 showed a close molecular fit with rimonabant in a CB1 receptor-based model. Compound 17 exhibited the highest CB1 receptor affinity (Ki = 24 nM) in this series, as well as very potent CB1 antagonistic activity (pA2 = 8.8) and a high CB1/CB2 subtype selectivity (approximately 147-fold). 相似文献
14.
Forbes IT Cooper DG Dodds EK Douglas SE Gribble AD Ife RJ Lightfoot AP Meeson M Campbell LP Coleman T Riley GJ Thomas DR 《Bioorganic & medicinal chemistry letters》2003,13(6):1055-1058
Novel 5-HT(7) receptor antagonists containing the benzocycloheptanone core were identified from high throughput screening. Molecular modelling and SAR studies have converted these intractable hits into a more potent, selective and tractable series, exemplified by compound (25), SB-691673. 相似文献
15.
Allan AC Billinton A Brown SH Chowdhury A Eatherton AJ Fieldhouse C Giblin GM Goldsmith P Hall A Hurst DN Naylor A Rawlings DA Sime M Scoccitti T Theobald PJ 《Bioorganic & medicinal chemistry letters》2011,21(14):4343-4348
We describe the discovery and optimization of a novel series of benzofuran EP1 antagonists, leading to the identification of 26d, a novel nonacidic EP1 antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain. 相似文献
16.
《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
17.
Ling A Plewe M Gonzalez J Madsen P Sams CK Lau J Gregor V Murphy D Teston K Kuki A Shi S Truesdale L Kiel D May J Lakis J Anderes K Iatsimirskaia E Sidelmann UG Knudsen LB Brand CL Polinsky A 《Bioorganic & medicinal chemistry letters》2002,12(4):663-666
A series of alkylidene hydrazide derivatives containing an alkoxyaryl moiety was optimized. The resulting hydrazide-ethers were competitive antagonists at the human glucagon receptor. Pharmacokinetic experiments showed fast clearance of most of the compounds tested. A representative compound [4-hydroxy-3-cyanobenzoic acid (4-isopropylbenzyloxy-3,5-dimethoxymethylene)hydrazide] with an IC50 value of 20 nM was shown to reduce blood glucose levels in fasted rats. 相似文献
18.
Bach P Boström J Brickmann K van Giezen JJ Hovland R Petersson AU Ray A Zetterberg F 《Bioorganic & medicinal chemistry letters》2011,21(10):2877-2881
A novel series of P2Y12 antagonists for development of drugs within the antiplatelet area is presented. The synthesis of the piperazinyl-pyridine urea derivatives and their structure-activity relationships (SAR) are described. Several compounds showed P2Y12 antagonistic activities in the sub-micromolar range. 相似文献
19.
Nian Zhou Wayne Zeller Michael Krohn Herb Anderson Jun Zhang Emmanuel Onua Alex S. Kiselyov Jose Ramirez Guðrún Halldorsdottir Þorkell Andrésson Mark E. Gurney Jasbir Singh 《Bioorganic & medicinal chemistry letters》2009,19(1):123-126
A series of potent and selective EP3 receptor antagonists are described. Utilizing a pharmacophore model developed for the EP3 receptor, a series of 3,4-disubstituted indoles were shown to be high affinity ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors and are potent antagonists in functional assays. 相似文献
20.
Sinz C Bittner A Brady E Candelore M Dallas-Yang Q Ding V Jiang G Lin Z Qureshi S Salituro G Saperstein R Shang J Szalkowski D Tota L Vincent S Wright M Xu S Yang X Zhang B Tata J Kim R Parmee ER 《Bioorganic & medicinal chemistry letters》2011,21(23):7124-7130
A novel class of N-aryl-2-acylindole human glucagon receptor (hGCGR) antagonists is reported. These compounds demonstrate good pharmacokinetic profiles in multiple preclinical species. One compound from this series, indole 33, is orally active in a transgenic murine pharmacodynamic model. Furthermore, a 1mg/kg oral dose of indole 33 lowers ambient glucose levels in an ob/ob/hGCGR transgenic murine diabetes model. This compound was deemed suitable for preclinical safety studies and was found to be well tolerated in an 8-day experimental rodent tolerability study. The combination of preclinical efficacy and safety observed with compound 33 highlights the potential of this class as a treatment for type 2 diabetes. 相似文献