共查询到20条相似文献,搜索用时 15 毫秒
1.
Smith RA Fathi Z Achebe F Akuche C Brown SE Choi S Fan J Jenkins S Kluender HC Konkar A Lavoie R Mays R Natoli J O'Connor SJ Ortiz AA Su N Taing C Tomlinson S Tritto T Wang G Wirtz SN Wong W Yang XF Ying S Zhang Z 《Bioorganic & medicinal chemistry letters》2007,17(10):2706-2711
Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 K(i)=3.7nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models. 相似文献
2.
Paula L. Nichols Jonathan Brand Michael Briggs Mathilde D’Angeli Jennifer Farge Stephen L. Garland Paul Goldsmith Rio Hutchings Ian Kilford Ho Y. Li David MacPherson Fiona Nimmo Francis Dominic Sanderson Sanjeet Sehmi Nicola Shuker John Skidmore Michael Stott Jennifer Sweeting Hasmi Tajuddin Andrew K. Takle David Witty 《Bioorganic & medicinal chemistry letters》2010,20(4):1368-1372
A pharmacophore model was built, based on known CGRP receptor antagonists, and this was used to aid the identification of novel leads. Analogues were designed, modelled and synthesised which incorporated alternative ‘LHS’ fragments linked via either an amide or urea to a privileged ‘RHS’ fragment commonly found in CGRP receptor antagonists. As a result a novel series of oxadiazole CGRP receptor antagonists has been identified and the subsequent optimisation to enhance both potency and bioavailability is presented. 相似文献
3.
Gil Nam Lee Kwang Rok Kim Sung-Hoon Ahn Myung Ae Bae Nam Sook Kang 《Bioorganic & medicinal chemistry letters》2010,20(17):5130-5132
In this work, we tried to find a new scaffold for a CB1 receptor antagonist using virtual screening. We first analyzed structural features for the known cannabinoid-1 receptor antagonists and, then, we built pharmacophore models using the HipHop concept and carried out a docking study based on our homology CB1 receptor 3D structure. The most active compound, including thiazole-4-one moiety, showed an activity value of 125 nM IC50, with a good PK profile. 相似文献
4.
A drug intended for use in humans should have an ideal balance of pharmacokinetics and safety, as well as potency and selectivity. Unfavorable pharmacokinetics can negatively affect the clinical development of many otherwise promising drug candidates. A variety of in silico ADME (absorption, distribution, metabolism, and excretion) models are receiving increased attention due to a better appreciation that pharmacokinetic properties should be considered in early phases of the drug discovery process. Human oral bioavailability is an important pharmacokinetic property, which is directly related to the amount of drug available in the systemic circulation to exert pharmacological and therapeutic effects. In the present work, hologram quantitative structure–activity relationships (HQSAR) were performed on a training set of 250 structurally diverse molecules with known human oral bioavailability. The most significant HQSAR model (q2 = 0.70, r2 = 0.93) was obtained using atoms, bond, connection, and chirality as fragment distinction. The predictive ability of the model was evaluated by an external test set containing 52 molecules not included in the training set, and the predicted values were in good agreement with the experimental values. The HQSAR model should be useful for the design of new drug candidates having increased bioavailability as well as in the process of chemical library design, virtual screening, and high-throughput screening. 相似文献
5.
Lavey BJ Kozlowski JA Shankar BB Spitler JM Zhou G Yang DY Shu Y Wong MK Wong SC Shih NY Wu J McCombie SW Rizvi R Wolin RL Lunn CA 《Bioorganic & medicinal chemistry letters》2007,17(13):3760-3764
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified. 相似文献
6.
Shankar BB Lavey BJ Zhou G Spitler JA Tong L Rizvi R Yang DY Wolin R Kozlowski JA Shih NY Wu J Hipkin RW Gonsiorek W Lunn CA 《Bioorganic & medicinal chemistry letters》2005,15(20):4417-4420
We recently reported that compound 1 is a potent inhibitor of the CB2 receptor with high selectivity over CB1. This paper describes the SAR development for this class of compounds. Variation of the substitution pattern on the aromatic rings, as well as the groups linking them together, led to sub-nanomolar inhibitors of the CB2 receptor, with high selectivity over CB1. 相似文献
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J Tam R Cinar J Liu G Godlewski D Wesley T Jourdan G Szanda B Mukhopadhyay L Chedester JS Liow RB Innis K Cheng KC Rice JR Deschamps RJ Chorvat JF McElroy G Kunos 《Cell metabolism》2012,16(2):167-179
Obesity-related leptin resistance manifests in loss of?leptin's ability to reduce appetite and increase energy expenditure. Obesity is also associated with increased activity of the endocannabinoid system, and CB(1) receptor (CB(1)R) inverse agonists reduce body weight and the associated metabolic complications, although adverse neuropsychiatric effects halted their therapeutic development. Here we show that in mice with diet-induced obesity (DIO), the peripherally restricted CB(1)R inverse agonist JD5037 is equieffective with its brain-penetrant parent compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance, even though it does not occupy central CB(1)R or induce related behaviors. Appetite and weight reduction by JD5037 are mediated by resensitizing DIO mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes and increasing leptin clearance via the?kidney. Thus, inverse agonism at peripheral CB(1)R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance. 相似文献
9.
Jong Yup Kim Hee Jeong Seo Sung-Han Lee Myung Eun Jung Kwangwoo Ahn Jeongmin Kim Jinhwa Lee 《Bioorganic & medicinal chemistry letters》2009,19(1):142-145
Since the CB1 receptor antagonist SR141716 (rimonabant) was reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target in the treatment of obesity. Several series of derivatives based on diarylimidazolyl oxadiazole and thiadiazole scaffolds were synthesized and tested for CB1 receptor binding affinity. SAR studies directed toward the optimization of imidazole scaffolds resulted in the discovery of 10s which showed highest potency for CB1 receptor binding affinity (IC50 = 1.91 nM) prepared to date. 相似文献
10.
Mihalic JT Chen X Fan P Chen X Fu Y Liang L Reed M Tang L Chen JL Jaen J Li L Dai K 《Bioorganic & medicinal chemistry letters》2011,21(23):7001-7005
A new class of MCHR1 antagonists was discovered via a high-throughput screen. Optimization of the lead structure resulted in the identification of indole 10e. This compound possesses good pharmacokinetic properties across preclinical species and is efficacious in reducing food consumption in an MCH cannulated rat model and a cynomolgus monkey food consumption model. 相似文献
11.
Synthesis and evaluation of urea-based indazoles as melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity 总被引:1,自引:0,他引:1
Souers AJ Gao J Wodka D Judd AS Mulhern MM Napier JJ Brune ME Bush EN Brodjian SJ Dayton BD Shapiro R Hernandez LE Marsh KC Sham HL Collins CA Kym PR 《Bioorganic & medicinal chemistry letters》2005,15(11):2752-2757
A series of urea-based N-1-(2-aminoethyl)-indazoles was synthesized and evaluated for melanin-concentrating hormone receptor 1 (MCHr1) antagonism in both binding and functional assays. Several compounds that acted as MCHr1 antagonists were identified, and optimization afforded a compound with excellent binding affinity, good functional potency, and oral efficacy in a chronic model for weight loss in diet-induced obese mice. 相似文献
12.
Marina Candido Primi Vinícius Gonçalves Maltarollo Juliana Gallottini Magalhães Matheus Malta de Sá Carlota Oliveira Rangel-Yagui 《Journal of enzyme inhibition and medicinal chemistry》2016,31(2):283-294
The dopamine hypothesis states that decreased dopaminergic neurotransmission reduces schizophrenia symptoms. Neurokinin-3 receptor (NK3) antagonists reduce dopamine release and have shown positive effects in pre-clinical and clinical trials. We employed 2D and 3D-QSAR analysis on a series of 40 non-peptide NK3 antagonists. Multivariate statistical analysis, PCA and HCA, were performed to rational training/test set splitting and PLS regression was employed to construct all QSAR models. We constructed one highly predictive CoMFA model (q2?=?0.810 and r2?=?0.929) and acceptable HQSAR and CoMSIA models (HQSAR q2?=?0.644 and r2?=?0.910; CoMSIA q2?=?0.691, r2?=?0.911). The three different techniques provided convergent physicochemical results. All models indicate cyclopropane, piperidine and di-chloro-phenyl ring attached to cyclopropane ring and also the amide group attached to the piperidine ring could play an important role in ligand–receptor interactions. These findings may contribute to develop potential NK3 receptor antagonists for schizophrenia. 相似文献
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《Bioorganic & medicinal chemistry letters》2019,29(21):126644
The cannabinoid-1 receptor (CB1R) inverse agonist SR141716A has proven useful for study of the endocannabinoid system, including development of divalent CB1R ligands possessing a second functional motif attached via a linker unit. These have predominantly employed the C3 position of the central pyrazole ring for linker attachment. Despite this precedent, a novel series of C3-linked CB1R-D2R divalent ligands exhibited extremely high affinity at the D2R, but only poor affinity for the CB1R. A systematic linker attachment point survey of the SR141716A pharmacophore was therefore undertaken, establishing the C5 position as the optimal site for linker conjugation. This linker attachment survey enabled the identification of a novel divalent ligand as a lead compound to inform ongoing development of high-affinity CB1R molecular probes. 相似文献
15.
Manuel de Lera Ruiz Junying Zheng Michael Y. Berlin Kevin D. McCormick Robert G. Aslanian Robert West Joyce Hwa Jean Lachowicz Margaret van Heek 《Bioorganic & medicinal chemistry letters》2013,23(21):6004-6009
A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test. 相似文献
16.
McCoull W Addie MS Birch AM Birtles S Buckett LK Butlin RJ Bowker SS Boyd S Chapman S Davies RD Donald CS Green CP Jenner C Kemmitt PD Leach AG Moody GC Gutierrez PM Newcombe NJ Nowak T Packer MJ Plowright AT Revill J Schofield P Sheldon C Stokes S Turnbull AV Wang SJ Whalley DP Wood JM 《Bioorganic & medicinal chemistry letters》2012,22(12):3873-3878
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship. 相似文献
17.
Ming Yu Mike Lizarzaburu Holger Beckmann Richard Connors Kang Dai Katrin Haller Cong Li Lingming Liang Michelle Lindstrom Ji Ma Alykhan Motani Malgorzata Wanska Alex Zhang Leping Li Julio C. Medina 《Bioorganic & medicinal chemistry letters》2010,20(5):1758-1762
Piperazine-bisamide analogs were discovered as partial agonists of human growth hormone secretagogue receptor (GHSR) in a high throughput screen. The partial agonists were optimized for potency and converted into antagonists through structure–activity relationship (SAR) studies. The efforts also led to the identification of potent antagonist with favorable PK profile suitable as a tool compound for in vivo studies. 相似文献
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Pandya T Pandey SK Tiwari M Chaturved SC Saxena AK 《Bioorganic & medicinal chemistry》2001,9(2):291-300
Essential structural and physicochemical requirements in terms of common biophoric sites (pharmacophore) and secondary sites for binding and interacting with AT1 and AT2 receptors have been identified using APEX-3-D expert system on 16 N2- aryl triazolinone biphenyl sulphonamides. Among several biophoric 3-D QSAR models two models (Nos. 1 and 2) having R2 > 0.7, chance <0.05 and match >0.5 and two models (Nos. 3 and 4) having R2 > 0.89, chance <0.03 and match >0.5 with three biophoric sites and two secondary sites (except model No. 4 with three secondary sites) describe the variation in AT1 and AT2 antagonistic activities, respectively. 相似文献
20.
John S. Debenham Christina B. Madsen-Duggan Junying Wang Xinchun Tong Julie Lao Tung M. Fong Marie-Therese Schaeffer Jing Chen Xiao Cathy C.R.-R. Huang Chun-Pyn Shen D. Sloan Stribling Lauren P. Shearman Alison M. Strack D. Euan MacIntyre Jeffrey J. Hale Thomas F. Walsh 《Bioorganic & medicinal chemistry letters》2009,19(9):2591-2594
The synthesis, SAR and binding affinities are described for cannabinoid-1 receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R. 相似文献