1、诺华的S1P 裂解酶抑制剂，可用于治疗复发性多发性硬化；2、诺华的瞬时受体电位A1离子通道(TRPA1)拮抗剂；3、默克的醛固酮合成酶(CYP11B2)抑制剂，CYP11B2是治疗醛固酮相关心脏疾病的新型靶点；4、辉瑞的5羟色胺2C(5-HT2C)受体激动剂；5、阿斯利康DprE1抑制剂。1. Orally Active 7-Substituted (4-Benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitriles as Active-Site Inhibitors of Sphingosine 1-Phosphate Lyase for the Treatment of Multiple SclerosisJ. Med. Chem., 2014, 57 (12), pp 5074–5084
DOI: 10.1021/jm500338n
公司/组织：诺华
候选药物化学结构式/活性：
靶点/作用机制：S1P 裂解酶抑制剂
摘要原文：
Sphingosine 1-phosphate (S1P) lyase has recently been implicated as a therapeutic target for the treatment of multiple sclerosis (MS), based on studies in a genetic mouse model. Potent active site directed inhibitors of the enzyme are not known so far. Here we describe the discovery of (4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitrile 5 in a high-throughput screen using a biochemical assay, and its further optimization. This class of compounds was found to inhibit catalytic activity of S1PL by binding to the active site of the enzyme, as seen in the cocrystal structure of derivative 31 with the homodimeric human S1P lyase. 31 induces profound reduction of peripheral T cell numbers after oral dosage and confers pronounced protection in a rat model of multiple sclerosis. In conclusion, this novel class of direct S1P lyase inhibitors provides excellent tools to further explore the therapeutic potential of T cell-targeted therapies in multiple sclerosis and other autoimmune and inflammatory diseases.
备注：
FTY720通过代谢激活后能拮抗S1P受体1，用于治疗复发性多发性硬化。
2. Discovery, Optimization, and Biological Evaluation of 5-(2-(Trifluoromethyl)phenyl)indazoles as a Novel Class of Transient Receptor Potential A1 (TRPA1) AntagonistsJ. Med. Chem., 2014, 57 (12), pp 5129–5140
DOI: 10.1021/jm401986p
公司/组织：诺华
候选药物化学结构式/活性：
靶点/作用机制：瞬时受体电位A1离子通道(TRPA1)拮抗剂
摘要原文：
A high throughput screening campaign identified 5-(2-chlorophenyl)indazole compound 4 as an antagonist of the transient receptor potential A1 (TRPA1) ion channel with IC50 = 1.23 μM. Hit to lead medicinal chemistry optimization established the SAR around the indazole ring system, demonstrating that a trifluoromethyl group at the 2-position of the phenyl ring in combination with various substituents at the 6-position of the indazole ring greatly contributed to improvements in vitro activity. Further lead optimization resulted in the identification of compound 31, a potent and selective antagonist of TRPA1 in vitro (IC50 = 0.015 μM), which has moderate oral bioavailability in rodents and demonstrates robust activity in vivo in several rodent models of inflammatory pain.
备注：
文献已报道的TRPA1拮抗剂
3. Novel Pyridyl- or Isoquinolinyl-Substituted Indolines and Indoles as Potent and Selective Aldosterone Synthase InhibitorsJ. Med. Chem., 2014, 57 (12), pp 5179–5189
DOI: 10.1021/jm500140c
公司/组织：默克
候选药物化学结构式/活性：
靶点/作用机制：醛固酮合成酶(CYP11B2)抑制剂
摘要原文：
Pathologically, high levels of aldosterone are associated with severe cardiovascular diseases such as congestive heart failure, hypertension, and myocardial fibrosis. The inhibition of aldosterone synthase (CYP11B2) to reduce aldosterone levels has been proposed as a promising treatment for diseases related to CYP11B2 because it is the crucial enzyme in the biosynthesis of aldosterone. A series of novel pyridyl- or isoquinolinyl-substituted indolines and indoles was designed via a ligand-based approach. The synthesized compounds were tested and found to be strong CYP11B2 inhibitors. The most potent ones showed IC50 values of less than 3 nM, being similarly potent as fadrozole and LCI699. Among them, compounds 14 and 23 showed good selectivity over the highly homologous CYP11B1, with selectivity factors (SF = IC50 CYP11B1/IC50 CYP11B2) around 170; thus, they are superior to fadrozole and LCI699 (SFs < 15). These potent CYP11B2 inhibitors exhibited no inhibition (IC50 > 50 μM) of a panel of hepatic CYP enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 and the crucial steroidogenic enzymes, CYP17 and CYP19. Because of these advantageous profiles, compounds 14 and 23 are considered to be candidates for further in vivo evaluation.
备注：
CYP11B2是治疗醛固酮相关心脏疾病的新型靶点。利用CYP11B2抑制剂效果可能优于目前使用的血管紧张素转化酶ACE抑制剂和盐皮质激素MR拮抗剂。
4. Multiparameter Optimization in CNS Drug Discovery: Design of Pyrimido[4,5-d]azepines as Potent 5-Hydroxytryptamine 2C (5-HT2C) Receptor Agonists with Exquisite Functional Selectivity over 5-HT2A and 5-HT2B ReceptorsJ. Med. Chem., 2014, 57 (12), pp 5258–5269
DOI: 10.1021/jm5003292
公司/组织：辉瑞
候选药物化学结构式/活性：
靶点/作用机制：5羟色胺2C(5-HT2C)受体激动剂
摘要原文：
A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.
备注：
部分5-HT2C激动剂
5. 4-Aminoquinolone Piperidine Amides: Noncovalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial ActivityJ. Med. Chem., 2014, 57 (12), pp 5419–5434
DOI: 10.1021/jm5005978
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：DprE1抑制剂
摘要原文：
4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequencing of mutants raised against AQs, identified decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) as the primary target responsible for the antitubercular activity. Mass spectrometry and enzyme kinetic studies indicated that AQs are noncovalent, reversible inhibitors of DprE1 with slow on rates and long residence times of 100 min on the enzyme. In general, AQs have excellent leadlike properties and good in vitro secondary pharmacology profile. Although the scaffold started off as a single active compound with moderate potency from the whole cell screen, structure–activity relationship optimization of the scaffold led to compounds with potent DprE1 inhibition (IC50 < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb.
备注：
(by 浮米网)
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