1、阿斯利康的PI3Kβ/δ抑制剂，抑制PI3Kβ被认为对PTEN缺失的肿瘤治疗很重要；3、诺华的丙肝病毒多聚酶抑制剂；4、药明康德的抗真菌药；7、默克的组织蛋白酶D抑制剂（Cathepsin D）1. Discovery of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumoursBioorganic & Medicinal Chemistry Letters 24 (2014) 3928–3935
DOI: 10.1016/j.bmcl.2014.06.040
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：PI3Kβ/δ抑制剂
摘要原文：
Starting from TGX-221, we designed a series of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as potent and selective PI3Kβ/δ inhibitors. Structure–activity relationships and structure–property relationships around the aniline and the amide substituents are discussed. We identified compounds 17 and 18, which showed profound pharmacodynamic modulation of phosphorylated Akt in the PC3 prostate tumour xenograft, after a single oral dose. Compound 17 also gave significant inhibition of tumour growth in the PC3 prostate tumour xenograft model after chronic oral dosing.
备注：
抑制PI3Kβ被认为对PTEN缺失的肿瘤治疗很重要。
2. Discovery of 9-(1-phenoxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as oral PI3Kβ inhibitors, useful as antiplatelet agentsBioorganic & Medicinal Chemistry Letters 24 (2014) 3936–3943
DOI: 10.1016/j.bmcl.2014.07.007
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：PI3Kβ抑制剂
摘要原文：
Optimization of AZD6482 (2), the first antiplatelet PI3Kβ inhibitor evaluated in man, focused on improving the pharmacokinetic profile to a level compatible with once daily oral dosing as well as achieving adequate selectivity towards PI3Kα to minimize the risk for insulin resistance. Structure-based design and optimization of DMPK properties resulted in (R)-16, a novel, orally bioavailable PI3Kβ inhibitor with potent in vivo anti-thrombotic effect with excellent separation to bleeding risk and insulin resistance.
备注：
3. Design and synthesis of lactam–thiophene carboxylic acids as potent hepatitis C virus polymerase inhibitorsBioorganic & Medicinal Chemistry Letters 24 (2014) 3979–3985
DOI: 10.1016/j.bmcl.2014.06.031
公司/组织：诺华
候选药物化学结构式/活性：
靶点/作用机制：丙肝病毒多聚酶抑制剂
摘要原文：
Herein we report the successful incorporation of a lactam as an amide replacement in the design of hepatitis C virus NS5B Site II thiophene carboxylic acid inhibitors. Optimizing potency in a replicon assay and minimizing potential risk for CYP3A4 induction led to the discovery of inhibitor 22a. This lead compound has a favorable pharmacokinetic profile in rats and dogs.
备注：
4. Scaffold hopping of sampangine: Discovery of potent antifungal lead compound against Aspergillus fumigatus and Cryptococcus neoformansBioorganic & Medicinal Chemistry Letters 24 (2014) 4090–4094
DOI: 10.1016/j.bmcl.2014.07.064
公司/组织：药明康德
候选药物化学结构式/活性：
靶点/作用机制：抗真菌药
摘要原文：
Discovery of novel antifungal agents against Aspergillus fumigatus and Cryptococcus neoformans remains a significant challenge in current antifungal therapy. Herein the antifungal natural product sampangine was used as the lead compound for novel antifungal drug discovery. A series of D-ring scaffold hopping derivatives were designed and synthesized to improve antifungal activity and water solubility. Among them, the thiophene derivative S2 showed broad-spectrum antifungal activity, particularly for Aspergillus fumigatus and Cryptococcus neoformans. Moreover, compound S2 also revealed better water solubility than sampangine, which represents a promising antifungal lead compound for further structural optimization.
备注：
侵略性的真菌感染致死率较高。目前抗真菌药物存在的主要问题包括：疗效低、窄谱、生物利用度低、高毒性和耐药性。
5. Discovery of pyrrolo-benzo-1,4-diazines as potent Nav1.7 sodium channel blockersBioorganic & Medicinal Chemistry Letters 24 (2014) 4110–4113
DOI: 10.1016/j.bmcl.2014.07.060
公司/组织：默克
候选药物化学结构式/活性：
靶点/作用机制：Nav1.7钠离子通道阻断剂
摘要原文：
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure–activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.
备注：
Nav1.7是电压门控钠离子通道，在疼痛神经元和交感神经节中高表达。它在小中型直径的感觉传入神经的产生和传导中发挥重要作用。
6. Kinase domain inhibition of leucine rich repeat kinase 2 (LRRK2) using a [1,2,4]triazolo[4,3-b]pyridazine scaffoldBioorganic & Medicinal Chemistry Letters 24 (2014) 4132–4140
DOI: 10.1016/j.bmcl.2014.07.052
公司/组织：辉瑞
候选药物化学结构式/活性：
靶点/作用机制：富亮氨酸重复激酶2抑制剂
摘要原文：
Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson’s disease (PD). The most common mutant, G2019S, increases kinase activity, thus LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the structure, potential ligand–protein binding interactions, and pharmacological profiling of potent and highly selective kinase inhibitors based on a triazolopyridazine chemical scaffold.
备注：
全基因组关联分析发现PARK8突变，编码富亮氨酸重复激酶2，与帕金森症相关。
7. Structure-based optimization of non-peptidic Cathepsin D inhibitorsBioorganic & Medicinal Chemistry Letters 24 (2014) 4141–4150
DOI: 10.1016/j.bmcl.2014.07.054
公司/组织：默克
候选药物化学结构式/活性：
靶点/作用机制：组织蛋白酶D抑制剂（Cathepsin D）
摘要原文：
We discovered a novel series of non-peptidic acylguanidine inhibitors of Cathepsin D as target for osteoarthritis. The initial HTS-hits were optimized by structure-based design using CatD X-ray structures resulting in single digit nanomolar potency in the biochemical CatD assay. However, the most potent analogues showed only micromolar activities in an ex vivo glycosaminoglycan (GAG) release assay in bovine cartilage together with low cellular permeability and suboptimal microsomal stability. This new scaffold can serve as a starting point for further optimization towards in vivo efficacy.
备注：
Cathepsin D 属于天冬氨酸蛋白酶家族，与肽键水解相关。
(by 浮米网)
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