Dihydropyrimidines: Novel Calcium Antagonists with Potent and Long-Lasting Vasodilative and Antihypertensive Activity

Hidetsura Cho; Masaru Ueda; Keivuu Shima; Akira Mizuno; Mariko Havashimatsu; Yoshiko Ohnaka; Yumi Takeuchi; Mikiko Hamaguchi; Kazuo Aisaka; Toshinori Hidaka; Masanori Kawai; Minako Takeda; Takafumi Ishihara; Kazuteru Funahashi; Fumio Satoh; Minoru Morita; Teruhisa Noguchi

doi:10.1021/jm00130a029

Dihydropyrimidines: Novel Calcium Antagonists with Potent and Long-Lasting Vasodilative and Antihypertensive Activity

Hidetsura Cho, Masaru Ueda, Keivuu Shima, Akira Mizuno, Mariko Havashimatsu, Yoshiko Ohnaka, Yumi Takeuchi, Mikiko Hamaguchi, Kazuo Aisaka, Toshinori Hidaka, Masanori Kawai, Minako Takeda, Takafumi Ishihara, Kazuteru Funahashi, Fumio Satoh, Minoru Morita, Teruhisa Noguchi

PHA - Molecular Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

177 Citations (Scopus)

Abstract

The novel calcium antagonists 3-N-substituted-3,4-dihydropyrimidines 1 and 9 and 3-N-substituted-dihydro-pyrimidin-2(lH)-ones 8 were regioselectively synthesized in good yields. Compounds 1 [especially 1s [R¹= (CH₂)₂ N(benzyl)(2-naphthylmethyl), R²= i-Pr, X = o-NO₂] and It [R¹= (CH₂)₂ N(benzyl)(3,4-dichlorobenzyl), R²= i-Pr, X = o-n O₂]] exhibited not only more potent and longer lasting vasodilative action but also a hypotensive activity with slow onset as compared with dihydropyridines. Moreover, some dihydropyrimidines [lq [R¹= (CH₂)₂ N(benzyl)(3-phenylpropyl), R²= CH₂(cyclopropyl), X = o-NO₂], Is, and It] were weaker in blocking atrioventricular conduction in anesthetized open-chest dogs and less toxic than the dihydropyridines.

Original language	English
Pages (from-to)	2399-2406
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	32
Issue number	10
DOIs	https://doi.org/10.1021/jm00130a029
Publication status	Published - 1989 Oct 1

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Cho, H., Ueda, M., Shima, K., Mizuno, A., Havashimatsu, M., Ohnaka, Y., Takeuchi, Y., Hamaguchi, M., Aisaka, K., Hidaka, T., Kawai, M., Takeda, M., Ishihara, T., Funahashi, K., Satoh, F., Morita, M., & Noguchi, T. (1989). Dihydropyrimidines: Novel Calcium Antagonists with Potent and Long-Lasting Vasodilative and Antihypertensive Activity. Journal of Medicinal Chemistry, 32(10), 2399-2406. https://doi.org/10.1021/jm00130a029

Dihydropyrimidines : Novel Calcium Antagonists with Potent and Long-Lasting Vasodilative and Antihypertensive Activity. / Cho, Hidetsura; Ueda, Masaru; Shima, Keivuu; Mizuno, Akira; Havashimatsu, Mariko; Ohnaka, Yoshiko; Takeuchi, Yumi; Hamaguchi, Mikiko; Aisaka, Kazuo; Hidaka, Toshinori; Kawai, Masanori; Takeda, Minako; Ishihara, Takafumi; Funahashi, Kazuteru; Satoh, Fumio; Morita, Minoru; Noguchi, Teruhisa.

In: Journal of Medicinal Chemistry, Vol. 32, No. 10, 01.10.1989, p. 2399-2406.

Research output: Contribution to journal › Article › peer-review

Cho, H, Ueda, M, Shima, K, Mizuno, A, Havashimatsu, M, Ohnaka, Y, Takeuchi, Y, Hamaguchi, M, Aisaka, K, Hidaka, T, Kawai, M, Takeda, M, Ishihara, T, Funahashi, K, Satoh, F, Morita, M & Noguchi, T 1989, 'Dihydropyrimidines: Novel Calcium Antagonists with Potent and Long-Lasting Vasodilative and Antihypertensive Activity', Journal of Medicinal Chemistry, vol. 32, no. 10, pp. 2399-2406. https://doi.org/10.1021/jm00130a029

Cho, Hidetsura ; Ueda, Masaru ; Shima, Keivuu ; Mizuno, Akira ; Havashimatsu, Mariko ; Ohnaka, Yoshiko ; Takeuchi, Yumi ; Hamaguchi, Mikiko ; Aisaka, Kazuo ; Hidaka, Toshinori ; Kawai, Masanori ; Takeda, Minako ; Ishihara, Takafumi ; Funahashi, Kazuteru ; Satoh, Fumio ; Morita, Minoru ; Noguchi, Teruhisa. / Dihydropyrimidines : Novel Calcium Antagonists with Potent and Long-Lasting Vasodilative and Antihypertensive Activity. In: Journal of Medicinal Chemistry. 1989 ; Vol. 32, No. 10. pp. 2399-2406.

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abstract = "The novel calcium antagonists 3-N-substituted-3,4-dihydropyrimidines 1 and 9 and 3-N-substituted-dihydro-pyrimidin-2(lH)-ones 8 were regioselectively synthesized in good yields. Compounds 1 [especially 1s [R1= (CH2)2 N(benzyl)(2-naphthylmethyl), R2= i-Pr, X = o-NO2] and It [R1= (CH2)2 N(benzyl)(3,4-dichlorobenzyl), R2= i-Pr, X = o-n O2]] exhibited not only more potent and longer lasting vasodilative action but also a hypotensive activity with slow onset as compared with dihydropyridines. Moreover, some dihydropyrimidines [lq [R1= (CH2)2 N(benzyl)(3-phenylpropyl), R2= CH2(cyclopropyl), X = o-NO2], Is, and It] were weaker in blocking atrioventricular conduction in anesthetized open-chest dogs and less toxic than the dihydropyridines.",

author = "Hidetsura Cho and Masaru Ueda and Keivuu Shima and Akira Mizuno and Mariko Havashimatsu and Yoshiko Ohnaka and Yumi Takeuchi and Mikiko Hamaguchi and Kazuo Aisaka and Toshinori Hidaka and Masanori Kawai and Minako Takeda and Takafumi Ishihara and Kazuteru Funahashi and Fumio Satoh and Minoru Morita and Teruhisa Noguchi",

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AU - Mizuno, Akira

AU - Havashimatsu, Mariko

AU - Ohnaka, Yoshiko

AU - Takeuchi, Yumi

AU - Hamaguchi, Mikiko

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AU - Hidaka, Toshinori

AU - Kawai, Masanori

AU - Takeda, Minako

AU - Ishihara, Takafumi

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AU - Satoh, Fumio

AU - Morita, Minoru

AU - Noguchi, Teruhisa

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N2 - The novel calcium antagonists 3-N-substituted-3,4-dihydropyrimidines 1 and 9 and 3-N-substituted-dihydro-pyrimidin-2(lH)-ones 8 were regioselectively synthesized in good yields. Compounds 1 [especially 1s [R1= (CH2)2 N(benzyl)(2-naphthylmethyl), R2= i-Pr, X = o-NO2] and It [R1= (CH2)2 N(benzyl)(3,4-dichlorobenzyl), R2= i-Pr, X = o-n O2]] exhibited not only more potent and longer lasting vasodilative action but also a hypotensive activity with slow onset as compared with dihydropyridines. Moreover, some dihydropyrimidines [lq [R1= (CH2)2 N(benzyl)(3-phenylpropyl), R2= CH2(cyclopropyl), X = o-NO2], Is, and It] were weaker in blocking atrioventricular conduction in anesthetized open-chest dogs and less toxic than the dihydropyridines.

AB - The novel calcium antagonists 3-N-substituted-3,4-dihydropyrimidines 1 and 9 and 3-N-substituted-dihydro-pyrimidin-2(lH)-ones 8 were regioselectively synthesized in good yields. Compounds 1 [especially 1s [R1= (CH2)2 N(benzyl)(2-naphthylmethyl), R2= i-Pr, X = o-NO2] and It [R1= (CH2)2 N(benzyl)(3,4-dichlorobenzyl), R2= i-Pr, X = o-n O2]] exhibited not only more potent and longer lasting vasodilative action but also a hypotensive activity with slow onset as compared with dihydropyridines. Moreover, some dihydropyrimidines [lq [R1= (CH2)2 N(benzyl)(3-phenylpropyl), R2= CH2(cyclopropyl), X = o-NO2], Is, and It] were weaker in blocking atrioventricular conduction in anesthetized open-chest dogs and less toxic than the dihydropyridines.

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Dihydropyrimidines: Novel Calcium Antagonists with Potent and Long-Lasting Vasodilative and Antihypertensive Activity

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