Fedi Valentina, Altamura Maria, Catalioto Rose-Marie, Giannotti Danilo, Giolitti Alessandro, Giuliani Sandro, Guidi Antonio, Harmat Nicholas J S, Lecci Alessandro, Meini Stefania, Nannicini Rossano, Pasqui Franco, Tramontana Manuela, Triolo Antonio, Maggi Carlo Alberto
Menarini Ricerche S.p.a., Via dei Sette Santi 3, I-50131 Florence, Italy.
J Med Chem. 2007 Oct 4;50(20):4793-807. doi: 10.1021/jm070289w. Epub 2007 Sep 12.
Starting from 1 (MEN14268), a selective tachykinin NK2 receptor antagonist with an interesting in vitro pharmacological profile, a family of numerous antagonists was obtained through an optimization process focused on iterated structural modifications. The effects of the introduction of a wide variety of substituents on the lipophilic aromatic part of the molecule and the modulation of the structural constraint through the insertion of different achiral alpha,alpha-dialkylamino acids were investigated. In particular, aromatic and benzofused heteroaromatic moieties were introduced at the pseudo-N-terminal residue to replace the 2-benzothiophene moiety, and a systematic investigation of the best positioning of substituents onto the aromatic platform was reported for the benzothiophene core. Studies on the modulation of the length and the rigidity of the hydrophilic pseudo-C-terminal pendant are presented. Many heteroaliphatic groups are well tolerated by the receptor in this part of the ligand. The product 48f (MEN15596), bearing a methyl substituent on the benzothiophene and a tetrahydropyranylmethylpiperidine pendant, was finally selected for its good in vivo activity after intravenous, intraduodenal, and oral administration in guinea pigs.
从1（MEN14268）开始，它是一种具有有趣体外药理学特性的选择性速激肽NK2受体拮抗剂，通过聚焦于迭代结构修饰的优化过程获得了一系列众多的拮抗剂。研究了在分子的亲脂性芳香部分引入各种取代基以及通过插入不同的非手性α，α-二烷基氨基酸来调节结构限制的影响。特别地，在假N端残基处引入芳香和苯并稠合杂芳基部分以取代2-苯并噻吩部分，并报道了针对苯并噻吩核心在芳香平台上取代基最佳定位的系统研究。还介绍了对亲水性假C端侧链长度和刚性调节的研究。在配体的这一部分，许多杂脂肪族基团受体耐受性良好。最终选择了在苯并噻吩上带有甲基取代基和四氢吡喃基甲基哌啶侧链的产物48f（MEN15596），因为它在豚鼠静脉内、十二指肠内和口服给药后具有良好的体内活性。
