1、杨森的代谢型谷氨酸受体2正向调节剂；2、阿斯利康的抗分枝杆菌药物；3、Amgen的磷酸二酯酶10A抑制剂；4、阿斯利康的抗疟疾先导化合物；5、Vertex Pharmaceuticals Inc的流感PB2抑制剂1.Discovery of 1-Butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone (JNJ-40411813): A Novel Positive Allosteric Modulator of the Metabotropic Glutamate 2 ReceptorJ. Med. Chem., 2014, 57 (15), pp 6495–6512
DOI: 10.1021/jm500496m
公司/组织：杨森
候选药物化学结构式/活性：
靶点/作用机制：代谢型谷氨酸受体2正向调节剂
摘要原文：
We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders.
备注：
谷氨酸是主要的神经递质，在中枢神经系统通过激活离子移变的谷氨酸受体iGlu和代谢型的谷氨酸受体mGlu调节突触反应。
2. Diarylthiazole: An Antimycobacterial Scaffold Potentially Targeting PrrB-PrrA Two-Component SystemJ. Med. Chem., 2014, 57 (15), pp 6572–6582
DOI: 10.1021/jm500833f
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：抗分枝杆菌
摘要原文：
Diarylthiazole (DAT), a hit from diversity screening, was found to have potent antimycobacterial activity against Mycobacterium tuberculosis (Mtb). In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to optimize the potency and physicochemical properties. The effort led to more than 10 compounds with submicromolar MICs and desirable physicochemical properties. The potent antimycobacterial activity, in conjunction with low molecular weight, made the series an attractive lead (antibacterial ligand efficiency (ALE) >0.4). The series exhibited excellent bactericidal activity and was active against drug-sensitive and resistant Mtb. Mutational analysis showed that mutations in prrB impart resistance to DAT compounds but not to reference drugs tested. The sensor kinase PrrB belongs to the PrrBA two component system and is potentially the target for DAT. PrrBA is a conserved, essential regulatory mechanism in Mtb and has been shown to have a role in virulence and metabolic adaptation to stress. Hence, DATs provide an opportunity to understand a completely new target system for antimycobacterial drug discovery.
备注：
肺结核药物研发的一个主要目标是找到具有新颖作用机制且能用于药物敏感性和耐药性的结核杆菌的抗生素。
3. Discovery of Clinical Candidate 1-(4-(3-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), A Potent, Selective, and Efficacious Inhibitor of Phosphodiesterase 10A (PDE10A)J. Med. Chem., 2014, 57 (15), pp 6632–6641
DOI: 10.1021/jm500713j
公司/组织：Amgen
候选药物化学结构式/活性：
靶点/作用机制：磷酸二酯酶10A抑制剂
摘要原文：
We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-acetyl piperazine 2 were changed by a single atom to tetrahydropyran 3 and N-acetyl piperidine 5. A second single atom modification from pyrazines 3 and 5 to pyridines 4 and 6 improved the inhibitory activity of 4 but not 6. In the in vivo LC–MS/MS target occupancy (TO) study at 10 mg/kg, 3, 5, and 6 achieved 86–91% occupancy of PDE10A in the brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral model were observed in a dose dependent manner. With superior in vivo TO, in vivo efficacy and in vivo PK profiles in multiple preclinical species, compound 5 (AMG 579) was advanced as our PDE10A clinical candidate.
备注：
磷酸二酯酶通过裂解磷酸二酯键能降低cNMP的水平。抑制PDE10A可以增加细胞内第二信使的水平。
4. N-Aryl-2-aminobenzimidazoles: Novel, Efficacious, Antimalarial Lead CompoundsJ. Med. Chem., 2014, 57 (15), pp 6642–6652
DOI: 10.1021/jm500715u
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：抗疟疾先导化合物
摘要原文：
From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the Pb malaria model. Compound 12 retains its potency against a panel of Pf isolates with known mechanisms of resistance. The fast killing observed in the in vitro parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria.
备注：
有些恶性疟原虫对一线抗疟药氯喹和磺胺-乙嘧啶耐药，严重阻碍了对疟疾的有效治疗。
5. Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2J. Med. Chem., 2014, 57 (15), pp 6668–6678
DOI: 10.1021/jm5007275
公司/组织：Vertex Pharmaceuticals Inc
候选药物化学结构式/活性：
靶点/作用机制：流感PB2抑制剂
摘要原文：
In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A.Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105−114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.
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