Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina 27709, United States.
J Med Chem. 2020 Sep 10;63(17):9563-9589. doi: 10.1021/acs.jmedchem.0c00745. Epub 2020 Aug 6.
Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y receptor (P2YR) antagonists were synthesized, and affinity was measured in P2YR-expressing Chinese hamster ovary cells by flow cytometry. Given this series' low water solubility, various polyethylene glycol derivatives of the distally binding piperidin-4-yl moiety of moderate affinity were synthesized. Rotation of previously identified 1,2,3-triazole attached to the central -benzoic acid core () provided moderate affinity but not indole and benzimidazole substitution of the aryl-triazole. The corresponding P2YR region is predicted by homology modeling as a deep, sterically limited hydrophobic pocket, with the outward pointing piperidine moiety being the most flexible. Bicyclic-substituted piperidine ring derivatives of naphthalene antagonist , e.g., quinuclidine (MRS4608, IC ≈ 20 nM at hP2YR/mP2YR), or of triazole , preserved affinity. Potent antagonists , , , and (10 mg/kg) protected in an ovalbumin/ mouse asthma model, and PEG conjugate reduced chronic pain. Thus, we expanded P2YR antagonist structure-activity relationship, introducing diverse physical-chemical properties.
各种杂芳基和双环脂肪族 P2Y 受体（P2YR）两性离子拮抗剂类似物被合成，并通过流式细胞术在表达 P2YR 的中国仓鼠卵巢细胞中测量亲和力。鉴于该系列的低水溶性，合成了具有中等亲和力的远端结合哌啶-4-基部分的各种聚乙二醇衍生物。先前鉴定的连接到中央 -苯甲酸核的 1,2,3-三唑的旋转提供了中等亲和力，但不是吲哚和苯并咪唑取代芳基-三唑。同源建模预测 P2YR 区域为一个深的、空间受限的疏水性口袋，向外指向的哌啶部分最灵活。萘拮抗剂 的双环取代哌啶环衍生物，例如喹诺啶 （MRS4608，在 hP2YR/mP2YR 上的 IC ≈ 20 nM），或三唑 ，保留了亲和力。有效拮抗剂 、 、 、 （10 mg/kg）在卵清蛋白/小鼠哮喘模型中具有保护作用，PEG 缀合物 减轻了慢性疼痛。因此，我们扩展了 P2YR 拮抗剂的结构-活性关系，引入了各种物理化学性质。
