1. Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant MutationsJ. Med. Chem., 2014, 57 (11), pp 4720–4744
DOI: 10.1021/jm500261q
公司/组织：辉瑞
候选药物化学结构式/活性：
靶点/作用机制：ALK & ROS1抑制剂
摘要原文：
Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.
备注：
2. Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase: Structure–Activity Relationships and Chiral Preference of a New Hydrophobic Binding RegionJ. Med. Chem., 2014, 57 (11), pp 4584–4597
DOI: 10.1021/jm500463c
公司/组织：阿斯利康
候选药物化学结构式/活性：
靶点/作用机制：胸苷酸激酶TMK抑制剂
摘要原文：
Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was employed to exploit a previously unexplored region in Staphylococcus aureus TMK via novel interactions. These efforts produced compound 39, with 3 nM IC50 against S. aureus TMK and 2 μg/mL MIC against methicillin-resistant S. aureus (MRSA). This compound exhibits a striking inverted chiral preference for binding relative to earlier compounds and also has improved physical properties and pharmacokinetics over previously published compounds. An example of this new series was efficacious in a murine S. aureus infection model, suggesting that compounds like 39 are options for further work toward a new Gram-positive antibiotic by maintaining a balance of microbiological potency, low clearance, and low protein binding that can result in lower efficacious doses.
备注：
解决抗生素耐药性的一个策略是研发具有新的作用模式或是作用于新型靶点的药物。细菌的TMK催化dTMP磷酸化成为dTDP，是与细菌存活息息相关的一个治疗靶点。
3. Efficacious Inhaled PDE4 Inhibitors with Low Emetic Potential and Long Duration of Action for the Treatment of COPDJ. Med. Chem., 2014, 57 (11), pp 4661–4676
DOI: 10.1021/jm5001216
公司/组织：阿斯利康
候选药物化学结构式/活性：
靶点/作用机制：PDE4抑制剂
摘要原文：
Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.
备注：
PDE4水解cAMP的磷酸二酯键，产生非活性AMP。PDE4的抑制剂能提高细胞内cAMP浓度，级联激活特定蛋白磷酸化通路，反过来减少一系列炎症介导物和炎症细胞功能。
4. Discovery of Pyrazolopyridones as a Novel Class of Noncovalent DprE1 Inhibitor with Potent Anti-Mycobacterial ActivityJ. Med. Chem., 2014, 57 (11), pp 4761–4771
DOI: 10.1021/jm5002937
公司/组织：阿斯利康
候选药物化学结构式/活性：
靶点/作用机制：非共价DprE1抑制剂
摘要原文：
A novel pyrazolopyridone class of inhibitors was identified from whole cell screening against Mycobacterium tuberculosis (Mtb). The series exhibits excellent bactericidality in vitro, resulting in a 4 log reduction in colony forming units following compound exposure. The significant modulation of minimum inhibitory concentration (MIC) against a Mtb strain overexpressing the Rv3790 gene suggested the target of pyrazolopyridones to be decaprenylphosphoryl-β-d-ribose-2′-epimerase (DprE1). Genetic mapping of resistance mutation coupled with potent enzyme inhibition activity confirmed the molecular target. Detailed biochemical characterization revealed the series to be a noncovalent inhibitor of DprE1. Docking studies at the active site suggest that the series can be further diversified to improve the physicochemical properties without compromising the antimycobacterial activity. The pyrazolopyridone class of inhibitors offers an attractive non-nitro lead series targeting the essential and vulnerable DprE1 enzyme for the discovery of novel antimycobacterial agents to treat both drug susceptible and drug resistant strains of Mtb.
备注：
DprE1是与阿拉伯半乳聚糖生物合成相关的关键酶，是分枝杆菌如结核杆菌存活的关键靶点。
5. Novel N-Linked Aminopiperidine-Based Gyrase Inhibitors with Improved hERG and in Vivo Efficacy against Mycobacterium tuberculosisJ. Med. Chem., 2014, 57 (11), pp 4889–4905
DOI: 10.1021/jm500432n
公司/组织：阿斯利康
候选药物化学结构式/活性：
靶点/作用机制：
DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, the prevalence of pre-existing resistance to FQs is likely to restrict their clinical value. We describe a novel class of N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting the DNA gyrase activity. The mechanism of inhibition of DNA gyrase was distinct from the fluoroquinolones, as shown by their ability to inhibit the growth of fluoroquinolone-resistant Mtb. Biochemical studies demonstrated this class to exert its action via single-strand cleavage rather than double-strand cleavage, as seen with fluoroquinolones. The compounds are highly bactericidal against extracellular as well as intracellular Mtb. Lead optimization resulted in the identification of potent compounds with improved oral bioavailability and reduced cardiac ion channel liability. Compounds from this series are efficacious in various murine models of tuberculosis.
摘要原文：
备注：
(by 浮米网)
|手机版|药群论坛
( 蜀ICP备15007902号 )
收藏
支持
反对
