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xingchen7_金蟲 (小有名氣)
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浮米每周文獻(xiàn)快訊：2014年3月（三） 已有1人參與
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1. Cathepsin C Inhibitors: Property Optimization and Identification of a Clinical Candidate. 期刊：J. Med. Chem., Article ASAP| Publication Date (Web): March 4, 2014 DOI: 10.1021/jm401705g 公司/組織：AstraZeneca 候選藥物化學(xué)結(jié)構(gòu)/活性：201403160101 靶點(diǎn)/作用機(jī)制：組織蛋白酶C (Cathepsin C)抑制劑 摘要原文：A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding. 備注：Cathepsin C是溶酶體半胱氨酸蛋白酶，與細(xì)胞內(nèi)蛋白降解有關(guān)。CatC的突變與常染色體遺傳性疾病Haim–Munck和Papillon–Lefèvre 綜合征有關(guān)。 2. 1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)indoline-4-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators. 期刊：J. Med. Chem., Article ASAP| Publication Date (Web): February 17, 2014 DOI: 10.1021/jm401625b 公司/組織：Pfizer 候選藥物化學(xué)結(jié)構(gòu)/活性：201403160102 靶點(diǎn)/作用機(jī)制：雄激素受體調(diào)節(jié)劑 摘要原文：We present a novel series of selective androgen receptor modulators (SARMs) which shows excellent biological activity and physical properties. 1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)-indoline-4-carbonitriles showed potent binding to the androgen receptor (AR) and activated AR-mediated transcription in vitro. Representative compounds demonstrated diminished activity in promoting the intramolecular interaction between the AR carboxyl (C) and amino (N) termini. This N/C-termini interaction is a biomarker assay for the undesired androgenic responses in vivo. In orchidectomized rats, daily administration of a lead compound from this series showed anabolic activity by increasing levator ani muscle weight. Importantly, minimal androgenic effects (increased tissue weights) were observed in the prostate and seminal vesicles, along with minimal repression of circulating luteinizing hormone (LH) levels and no change in the lipid and triglyceride levels. This lead compound completed a two week rat toxicology study, and was well tolerated at doses up to 100 mg/kg/day, the highest dose tested, for 14 consecutive days. 備注：雄激素受體調(diào)節(jié)通路與許多生物功能相關(guān)。雄激素受體調(diào)節(jié)劑對(duì)多種肌肉萎縮性疾病和癥狀具有潛在治療效果，包括肌肉減少癥、虛弱、精神萎縮。 3. Discovery of a Tetracyclic Quinoxaline Derivative as a Potent and Orally Active Multifunctional Drug Candidate for the Treatment of Neuropsychiatric and Neurological Disorders 期刊：J. Med. Chem., Article ASAP| Publication Date (Web): February 21, 2014 DOI: 10.1021/jm401958n 公司/組織：Bristol-Myers Squibb 候選藥物化學(xué)結(jié)構(gòu)/活性：201403160103 靶點(diǎn)/作用機(jī)制：5 -羥色胺2A (Serotonin 5-HT2A) & 多巴胺D2受體拮抗劑 摘要原文：We report the synthesis and structure–activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT2A and dopamine D2 receptors. This work has led to the discovery of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which is a potent 5-HT2A antagonist, postsynaptic D2 antagonist, and inhibitor of serotonin transporter. This multifunctional drug candidate is orally bioavailable and exhibits good antipsychotic efficacy in vivo. Currently, this investigational new drug is under clinical development for the treatment of neuropsychiatric and neurological disorders. 備注：精神分裂嚴(yán)重影響個(gè)人及社會(huì)。第一代抗精神病藥包括氯丙嗪和氟哌啶醇都是多巴胺D2受體拮抗劑。這類藥物的使用會(huì)產(chǎn)生錐體外系癥狀，包括遲發(fā)性神經(jīng)肌肉紊亂和高泌乳素血癥。這類藥物在發(fā)揮藥效的同時(shí)也可能會(huì)造成認(rèn)知障礙。第二代抗精神病藥作為5 -羥色胺2A和多巴胺D2受體拮抗劑，同時(shí)對(duì)兩個(gè)靶點(diǎn)產(chǎn)生拮抗作用保證了此類藥物的抗精神病效果。 4. Selective and Potent Morpholinone Inhibitors of the MDM2–p53 Protein–Protein Interaction. 期刊：J. Med. Chem., Article ASAP| Publication Date (Web): February 18, 2014 DOI: 10.1021/jm401767k 公司/組織：Amgen 候選藥物化學(xué)結(jié)構(gòu)/活性：201403160104 靶點(diǎn)/作用機(jī)制：MDM2抑制劑 摘要原文：We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2–p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein. 備注：MDM2過(guò)表達(dá)能阻斷p53介導(dǎo)的細(xì)胞周期停滯和細(xì)胞凋亡。阻斷MDM2與p53的結(jié)合已作為激活p53抑癌基因通路的有效途徑。許多阻斷MDM2-p53相互作用的小分子抑制劑已進(jìn)入臨床試驗(yàn)。 5. The Discovery of N-((2H-Tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822): A Potent and Selective Glucagon Receptor Antagonist. 期刊：J. Med. Chem., Article ASAP| Publication Date (Web): February 14, 2014 DOI: 10.1021/jm401858f 公司/組織：Merck 候選藥物化學(xué)結(jié)構(gòu)/活性：201403160105 靶點(diǎn)/作用機(jī)制：胰高血糖素受體(hGCGR)拮抗劑 摘要原文：A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound 1, N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over the human glucagon-like peptide-1 receptor. Oral administration of 1 lowered 24 h nonfasting glucose levels in imprinting control region mice on a high fat diet with diet-induced obesity following single oral doses of 3 and 10 mg/kg. Furthermore, compound 1, when dosed orally, was found to decrease fasting blood glucose at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose excursion in prediabetic mice. 備注：據(jù)國(guó)際糖尿病聯(lián)合會(huì)公布，2013年共有3.82億患者遭受糖尿病折磨，估計(jì)25年內(nèi)，患者人數(shù)將增加至5.92億。胰高血糖素受體在調(diào)節(jié)血清中葡萄糖水平上發(fā)揮重要作用。利用胰高血糖素受體拮抗劑可望治療II型糖尿病。 6. Discovery and SAR of 6-Alkyl-2,4-diaminopyrimidines as Histamine H4 Receptor Antagonists 期刊：J. Med. Chem., Article ASAP| Publication Date (Web): February 4, 2014 DOI: 10.1021/jm401727m 公司/組織：楊森Janssen Research & Development 候選藥物化學(xué)結(jié)構(gòu)/活性：201403160106 靶點(diǎn)/作用機(jī)制：組胺H4拮抗劑 摘要原文： This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects. 備注： 組胺受體屬于GPCR家族。組胺H4受體主要在免疫系統(tǒng)相關(guān)細(xì)胞中表達(dá)。臨床前動(dòng)物實(shí)驗(yàn)表明H4R拮抗劑可有望用于治療哮喘、風(fēng)濕性關(guān)節(jié)炎、異位性皮炎和其他免疫相關(guān)炎性疾病。 （by 浮米網(wǎng)） |
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至尊木蟲 (著名寫手)
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