Kubota H, Fujii M, Ikeda K, Takeuchi M, Shibanuma T, Isomura Y
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Chem Pharm Bull (Tokyo). 1998 Feb;46(2):351-4. doi: 10.1248/cpb.46.351.
Analysis of the structural requirements of compound 1 (SR48968), a potent NK2 receptor antagonist, revealed that the 4-phenyl group of the piperidine is essential for binding with the NK2 receptor and occupies an equatorial position. Energy calculation of a variety of substituted 4-phenyl piperidines revealed that spiro[isobenzofuran-1(3H),4'-piperidine] possesses a conformationally restricted equatorial phenyl group. Our compound 12 (YM-35375) possessing this spiro-substituted piperidine bound to the NK2 receptor with an IC50 value of 84 nM and to the NK1 receptor with an IC50 value of 710 nM. It showed more potent inhibitory activity (ID50 41 micrograms/kg (i.v.)) against [beta-Ala8]-NKA(4-10)-induced bronchoconstriction in guinea pigs than (+/-)-SR48968 (ID50 68 micrograms/kg (i.v.)). YM-35375 may be a new lead compound for novel NK2 receptor antagonists or NK1-NK2 dual antagonists.
强效NK2受体拮抗剂化合物1（SR48968）的结构要求分析表明，哌啶的4-苯基对于与NK2受体结合至关重要，且占据赤道位置。对多种取代的4-苯基哌啶进行能量计算表明，螺[异苯并呋喃-1(3H),4'-哌啶]具有构象受限的赤道苯基。我们的具有这种螺取代哌啶的化合物12（YM-35375）与NK2受体结合的IC50值为84 nM，与NK1受体结合的IC50值为710 nM。它对豚鼠体内[β-丙氨酸8]-NKA(4-10)诱导的支气管收缩表现出比(±)-SR48968更强的抑制活性（静脉注射ID50为41微克/千克，而(±)-SR48968静脉注射ID50为68微克/千克）。YM-35375可能是新型NK2受体拮抗剂或NK1-NK2双重拮抗剂的新先导化合物。
