Kaminski J J, Carruthers N I, Wong S C, Chan T M, Billah M M, Tozzi S, McPhail A T
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Bioorg Med Chem. 1999 Jul;7(7):1413-23. doi: 10.1016/s0968-0896(99)00075-9.
Following the discovery of the first dual antagonist of platelet-activating factor (PAF) and histamine, 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin- 11-ylidene)piperidine, Sch 37370, 1, a related series of structures, exemplified by (+/-)-1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b] pyridin-11-yl)piperazine, Sch 40338, 2, were prepared. Interestingly, the compounds exhibited a parallel structure antiallergy activity relationship, suggesting that the two series may adopt a common conformation at the PAF receptor. Conformational analysis led to a proposal for this bioactive conformation accessible to both series. The synthesis of novel conformationally constrained analogues that might mimic the proposed bioactive conformation of these compounds, and the evaluation of their in vitro antiallergy activity form the subject matter of this report.
继发现首个血小板活化因子（PAF）和组胺双重拮抗剂1-乙酰基-4-（8-氯-5,6-二氢-11H-苯并[5,6]环庚并[1,2-b]吡啶-11-亚基）哌啶（Sch 37370，1）之后，制备了一系列相关结构，以（±）-1-乙酰基-4-（8-氯-5,6-二氢-11H-苯并[5,6]环庚并[1,2-b]吡啶-11-基）哌嗪（Sch 40338，2）为代表。有趣的是，这些化合物呈现出平行的结构-抗过敏活性关系，表明这两个系列可能在PAF受体处采用共同构象。构象分析得出了这两个系列均可达到的这种生物活性构象的提议。本报告的主题是合成可能模拟这些化合物提议的生物活性构象的新型构象受限类似物，并评估它们的体外抗过敏活性。
