Spiro-Substituted Piperidines as Neurokinin Receptor Antagonists. III. Synthesis of (.+-.)-N-12-(3,4-Dichlorophenyl)-4-(spiro-substituted piperidin-1-yl)butyll-N-methylbenzamides and Evaluation of NK1-NK2 Dual Antagonistic Activities.

Q4 · MEDICINE

Article

Author: Orita, Masaya ; Takeuchi, Makoto ; Okamoto, Yoshinori ; Yamamoto, Osamu ; Fujii, Masahiro ; Yamagiwa, Yoko ; Ikeda, Ken ; Shibanuma, Tadao ; Kubota, Hirokazu ; Kakefuda, Akio ; Isomura, Yasuo

To discover a novel NK1-NK2 dual antagonist, we have synthesized a series of spiro-substituted piperidines utilizing YM-35375 as a lead compound, and evaluated affinities for NK1 and NK2 receptors. In the N-methylbenzamide moiety, introduction of methoxy groups increased affinity for the NK1 receptor without a significant loss of affinity for the NK2 receptor. We also found that a conformation in which the phenyl groups of the N-methylbenzamide and 3,4-dichlorophenyl moieties are close to each other through a cis-amide bond, may be favorable for showing high affinity for the NK1 receptor and that a hydrogen bond-accepting group in the spiro-substituted piperidine moiety may be crucial for exhibiting high affinity for the NK2 receptor. Among the compounds prepared, YM-44778 (31) showed high and well-balanced affinity for NK1 and NK2 receptors (IC50 values of 18 and 16 nM, respectively). This compound also exhibited potent antagonistic activities against both NK1 and NK2 receptors (IC50 values of 82 and 62 nM, respectively) in isolated tissues.

01 Jan 1998·Chemical and Pharmaceutical BulletinQ4 · MEDICINE

Spiro-Substituted Piperidines as Neurokinin Receptor Antagonists. II. Syntheses and NK2 Receptor-Antagonistic Activities of N-(2-Aryl-4-(spiro-substituted piperidin-1'-yl)butyl)carboxamides.

Q4 · MEDICINE

Article

Author: Yamamoto, Osamu ; Takeuchi, Makoto ; Kafefuda, Akio ; Nagaoka, Hitoshi ; Shibanuma, Tadao ; Isomura, Yasuo ; Ikeda, Ken ; Kubota, Hirokazu

In the course of our research on spiro-compounds as neurokinin receptor antagonists, N-[2-aryl-4-(spiro-substituted piperidin-1'-yl)butyl]carboxamides were designed, based on YM-35375 (3) as a lead compound, and evaluated for NK2 receptor-antagonistic activities. Some derivatives inhibited the binding of radio-labeled neurokinin A to the NK2 receptor with IC50 values at the level of 10(-9) M. Among these compounds, (+/-)-1'-[4-(N-benzoyl-N-methylamino)-3- (3,4-dichlorophenyl)butyl]spiro[benzo[c]thiophene-1(3H), 4'-piperidine] 2-oxide (58, YM-38336) showed 10 times more potent NK2 receptor binding affinity than compound 3 (IC50 values of 8.9 and 84 nM, respectively). It showed more potent inhibitory activity (ID50 20 micrograms/kg (i.v.)) against [beta-Ala8]-NKA(4-10)-induced bronchoconstriction in guinea pigs than compound 3 (ID50 41 micrograms/kg (i.v.)). This compound was also effective intraduodenally in the same model, exhibiting an ID50 value of 0.41 microgram/kg.

01 Jan 1998·Chemical and Pharmaceutical BulletinQ4 · MEDICINE

Spiro-Substituted Piperidines as Neurokinin Receptor Antagonists. I. Design and Synthesis of (.+-.)-N-(2-(3,4-Dichlorophenyl)-4-(spiro(isobenzofuran-1(3H),4'-piperidin)-1'-yl)butyl)-N-methylbenzamide, YM-35375, as a New Lead Compound for Novel Neurokinin Receptor Antagonists.

Q4 · MEDICINE

Article

Author: Fujii, Masahiro ; Shibanuma, Tadao ; Takeuchi, Makoto ; Isomura, Yasuo ; Kubota, Hirokazu ; Ikeda, Ken

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	NDA/BLA	JP	Yamanouchi Pharmaceutical Co., Ltd.	-
Irritable Bowel Syndrome	Discovery	JP	Yamanouchi Pharmaceutical Co., Ltd.	-
Urinary Incontinence	Discovery	JP	Yamanouchi Pharmaceutical Co., Ltd.	-

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