上周各大制药企业在JMC上发表了四篇文章：1、辉瑞的Pin1抑制剂，Pin1是治疗癌症的一个潜在靶点，在细胞周期调节中发挥重要作用；2、诺华的β0032肾上腺素能受体激动剂，用于治疗COPD；3、Arena Pharmaceuticals Inc.的GPR119激动剂，以治疗II型糖尿病；4、Actelion Pharmaceuticals Ltd的P2Y12拮抗剂，ADP受体P2Y12在血小板激活和聚集中发挥重要作用。
1. Structure-based design of novel human Pin1 inhibitors (III): Optimizing affinity beyond the phosphate recognition pocketDOI: 10.1016/j.bmcl.2014.07.044
公司/组织：辉瑞
候选药物化学结构式/活性：
靶点/作用机制：Pin1抑制剂
摘要原文：
The design of potent Pin1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based Pin1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been previously reported. The potency of the carboxylate series is now further improved through structure-based optimization of ligand–protein interactions in the proline binding site which exploits the H-bond interactions necessary for Pin1 catalytic function. Further optimization using a focused library approach led to the discovery of low nanomolar non-phosphate small molecular Pin1 inhibitors. Structural modifications designed to improve cell permeability resulted in Pin1 inhibitors with low micromolar anti-proliferative activities against cancer cells.
备注：
Pin1是治疗癌症的一个潜在靶点，在细胞周期调节中发挥重要作用。
2. The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting β2-adrenoceptor agonistBioorganic & Medicinal Chemistry Letters 24 (2014) 4341–4347
DOI: 10.1016/j.bmcl.2014.06.014
公司/组织：诺华
候选药物化学结构式/活性：
靶点/作用机制：β0032肾上腺素能受体激动剂
摘要原文：
The optimisation of two series of 4-hydroxybenzothiazolone derived β2-adrenoceptor agonists, bearing α-substituted cyclopentyl and β-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting β2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.
备注：
用于治疗COPD。
3. Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonistsDOI: 10.1016/j.bmcl.2014.06.071
公司/组织：Arena Pharmaceuticals Inc.
候选药物化学结构式/活性：
靶点/作用机制：GPR119激动剂
摘要原文：
A series of 5-fluoro-4,6-dialkoxypyrimidine GPR119 modulators were discovered and optimized for in vitro agonist activity. A lead molecule was identified that has improved agonist efficacy relative to our clinical compound (APD597) and possesses reduced CYP2C9 inhibitory potential. This optimized lead was found to be efficacious in rodent models of glucose control both alone and in combination with a Dipeptidyl peptidase-4 (DPP-4) inhibitor.
备注：
GPR119的激活与GLP-1和GIP的释放相关，作用于β细胞促进葡萄糖依赖性的胰岛素释放。研发GPR119激动剂以治疗II型糖尿病。
4. Optimization of 2-phenyl-pyrimidine-4-carboxamides towards potent, orally bioavailable and selective P2Y12 antagonists for inhibition of platelet aggregationBioorganic & Medicinal Chemistry Letters 24 (2014) 4323–4331
DOI: 10.1016/j.bmcl.2014.06.070
公司/组织：Actelion Pharmaceuticals Ltd
候选药物化学结构式/活性：
靶点/作用机制：P2Y12拮抗剂
摘要原文：
2-Phenyl-pyrimidine-4-carboxamide analogs were identified as P2Y12 antagonists. Optimization of the carbon-linked or nitrogen-linked substituent at the 6-position of the pyrimidine ring provided compounds with excellent ex vivo potency in the platelet aggregation assay in human plasma. Compound 23u met the objectives for activity, selectivity and ADMET properties.
备注：
ADP受体P2Y12在血小板激活和聚集中发挥重要作用。
(by 浮米网)
