Thévenin Marion, Chen Gang, Kantham Srinivas, Sun Chunxiang, Glogauer Michael, Young Robert N
Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5Z 4B4, Canada.
Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, Ontario M5S 3E2, Canada.
ACS Pharmacol Transl Sci. 2021 Mar 10;4(2):908-925. doi: 10.1021/acsptsci.1c00027. eCollection 2021 Apr 9.
A series of bone-targeting EP4 receptor agonist conjugate prodrugs were prepared wherein a potent EP4 receptor agonist was bound to a biologically inactive, bisphosphonate-based bone-targeting moiety. Singly and doubly radiolabeled conjugates were synthesized and were shown to be stable in blood, to be rapidly eliminated from the bloodstream, and to be effectively taken up into bone in vivo after intravenous dosing. From these preliminary studies a preferred conjugate (also known as and Mes-1007) was selected for follow up biodistribution and elimination studies. Doubly radiolabeled conjugate was found to partition largely to the liver and bones, and both labels were eliminated from liver at the same rate indicating the conjugate was eliminated intact. Quantification of the labels in bones indicated that free EP4 agonist (EP4a)() was released from bone-bound with a half-time of about 7 days. When dosed orally, radiolabeled was not absorbed and passed through the gastrointestinal tract essentially unchanged, and only traces of radiolabeled were found in the liver, blood, or bones. was found to bind rapidly and completely to powdered bone mineral or to various forms of calcium phosphate, forming a stable matrix suitable for implant and that could made into powders or solid forms and be sterilized without decomposition or release of . Basic hydrolysis released free EP4 agonist quantitatively from the material.
制备了一系列骨靶向EP4受体激动剂共轭前药,其中一种强效EP4受体激动剂与一种无生物活性的、基于双膦酸盐的骨靶向部分相连。合成了单标记和双标记的共轭物,结果表明它们在血液中稳定,能迅速从血流中清除,静脉给药后在体内能有效摄取到骨骼中。从这些初步研究中,选择了一种优选的共轭物(也称为Mes-1007)进行后续的生物分布和清除研究。发现双标记的共轭物主要分布在肝脏和骨骼中,两种标记物从肝脏中以相同的速率清除,表明共轭物完整地被清除。骨骼中标记物的定量分析表明,游离的EP4激动剂(EP4a)从与骨结合的共轭物中释放出来的半衰期约为7天。口服给药时,放射性标记的共轭物未被吸收,基本上未改变地通过胃肠道,在肝脏、血液或骨骼中仅发现微量的放射性标记共轭物。发现共轭物能迅速且完全地与粉末状骨矿物质或各种形式的磷酸钙结合,形成适合植入的稳定基质,可制成粉末或固体形式,并可进行灭菌而不会分解或释放共轭物。碱性水解从该材料中定量释放出游离的EP4激动剂。