1. 原文标题及出处：Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Aacid Isosteres.
J. Med. Chem., 2014, 57 (7), pp 2963–2988
DOI: 10.1021/jm401911v
公司/组织：Amgen Inc.
候选药物化学结构式/活性：
靶点/作用机制：MDM2抑制剂，阻断MDM2-p53相互作用
摘要原文：
We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.
2. 原文标题及出处：Optimization of Potency and Pharmacokinetic Properties of Tetrahydroisoquinoline Transient Receptor Potential Melastatin 8 (TRPM8) Antagonists
J. Med. Chem., 2014, 57 (7), pp 2989–3004
DOI: 10.1021/jm401955h
公司/组织：Amgen Inc.
候选药物化学结构式/活性：
靶点/作用机制：TRPM8拮抗剂
摘要原文：
Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 °C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values <3 mg/kg.
备注：TRPM8是离子通道蛋白，被认为是治疗疼痛以膀胱疼痛、过度活跃综合征。
3. 原文标题及出处：Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 3. Structure–Activity Relationships within the Aryl Carbinol Region of the N-Arylsulfonamido-N′-arylpiperazine Series
J. Med. Chem., 2014, 57 (7), pp 3094–3116
DOI: 10.1021/jm5000497
公司/组织：Amgen Inc.
候选药物化学结构式/活性：
靶点/作用机制：葡萄糖激酶调节蛋白
摘要原文：
We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, glucokinase regulatory protein (GKRP). These initial investigations culminated in the identification of
2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK–GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lowered fed blood glucose levels (up to 58%).
备注：葡萄糖激酶(GK)参与葡萄糖平衡的调控，其活性受GKRP的调节。通过阻断GK-GKRP相互作用能达到降血糖的目的。
(by 浮米网)
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