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xingchen7_金虫 (小有名气)
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浮米每周文献快讯：2014年3月（三）已有1人参与
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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/组织：AstraZeneca 候选药物化学结构/活性：201403160101 靶点/作用机制：组织蛋白酶C (Cathepsin C)抑制剂 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. 备注：Cathepsin C是溶酶体半胱氨酸蛋白酶，与细胞内蛋白降解有关。CatC的突变与常染色体遗传性疾病Haim–Munck和Papillon–Lefèvre 综合征有关。 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/组织：Pfizer 候选药物化学结构/活性：201403160102 靶点/作用机制：雄激素受体调节剂 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. 备注：雄激素受体调节通路与许多生物功能相关。雄激素受体调节剂对多种肌肉萎缩性疾病和症状具有潜在治疗效果，包括肌肉减少症、虚弱、精神萎缩。 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/组织：Bristol-Myers Squibb 候选药物化学结构/活性：201403160103 靶点/作用机制：5 -羟色胺2A (Serotonin 5-HT2A) & 多巴胺D2受体拮抗剂 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. 备注：精神分裂严重影响个人及社会。第一代抗精神病药包括氯丙嗪和氟哌啶醇都是多巴胺D2受体拮抗剂。这类药物的使用会产生锥体外系症状，包括迟发性神经肌肉紊乱和高泌乳素血症。这类药物在发挥药效的同时也可能会造成认知障碍。第二代抗精神病药作为5 -羟色胺2A和多巴胺D2受体拮抗剂，同时对两个靶点产生拮抗作用保证了此类药物的抗精神病效果。 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/组织：Amgen 候选药物化学结构/活性：201403160104 靶点/作用机制：MDM2抑制剂 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. 备注：MDM2过表达能阻断p53介导的细胞周期停滞和细胞凋亡。阻断MDM2与p53的结合已作为激活p53抑癌基因通路的有效途径。许多阻断MDM2-p53相互作用的小分子抑制剂已进入临床试验。 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/组织：Merck 候选药物化学结构/活性：201403160105 靶点/作用机制：胰高血糖素受体(hGCGR)拮抗剂 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. 备注：据国际糖尿病联合会公布，2013年共有3.82亿患者遭受糖尿病折磨，估计25年内，患者人数将增加至5.92亿。胰高血糖素受体在调节血清中葡萄糖水平上发挥重要作用。利用胰高血糖素受体拮抗剂可望治疗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/组织：杨森Janssen Research & Development 候选药物化学结构/活性：201403160106 靶点/作用机制：组胺H4拮抗剂 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. 备注： 组胺受体属于GPCR家族。组胺H4受体主要在免疫系统相关细胞中表达。临床前动物实验表明H4R拮抗剂可有望用于治疗哮喘、风湿性关节炎、异位性皮炎和其他免疫相关炎性疾病。 （by 浮米网） |
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