Carter Percy H, Brown Gregory D, Cherney Robert J, Batt Douglas G, Chen Jing, Clark Cheryl M, Cvijic Mary Ellen, Duncia John V, Ko Soo S, Mandlekar Sandhya, Mo Ruowei, Nelson David J, Pang Jian, Rose Anne V, Santella Joseph B, Tebben Andrew J, Traeger Sarah C, Xu Songmei, Zhao Qihong, Barrish Joel C
Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.
ACS Med Chem Lett. 2015 Mar 4;6(4):439-44. doi: 10.1021/ml500505q. eCollection 2015 Apr 9.
We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a new series of dual antagonists of CCR2 and CCR5. Installation of a γ-lactam as the spacer group and a quinazoline as a benzamide mimetic improved oral bioavailability markedly. These efforts led to the identification of 13d, a potent and orally bioavailable dual antagonist suitable for use in both murine and monkey models of inflammation.
我们描述了我们之前报道的非环状和环状C-C趋化因子受体2（CCR2）拮抗剂的杂交，从而产生了一系列新的CCR2和CCR5双重拮抗剂。引入γ-内酰胺作为间隔基团以及喹唑啉作为苯甲酰胺模拟物显著提高了口服生物利用度。这些研究工作导致了13d的鉴定，13d是一种强效且口服生物可利用的双重拮抗剂，适用于小鼠和猴子的炎症模型。
