Structure–activity relationship study of 1,4-dihydropyridine derivatives blocking N-type calcium channels

Yamamoto, Takashi; Niwa, Seiji; Ohno, Seiji; Onishi, Taku; Matsueda, Hiroyuki; Koganei, Hajime; Uneyama, Hisayuki; Fujita, Shin-ichi; Takeda, Tomoko; Kito, Morikazu; Ono, Yukitsugu; Saitou, Yuki; Takahara, Akira; Iwata, Seiichi; Shoji, Masataka

doi:10.1016/j.bmcl.2005.11.021

Cited by 34 publications

(12 citation statements)

References 24 publications

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“…9), a slow-onset, long-lasting hypotensive 1,4-DHP, to inhibit the Ca V 2.2 (N-Type) channels that are implicated in the neuropathic pain [72]. More recently, Yamamoto et al synthesized and tested a series of cilnidipine analogs blocking Ntype calcium channels [73]. Starting from cilnidipine and APJ2708 ( Fig.…”

Section: Activity Of 14-dhps On N-type Calcium Channelsmentioning

confidence: 99%

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story so Far And Perspectives (Part 1): Action in Ion Channels and GPCRs

Ioan¹,

Carosati²,

Micucci³

et al. 2011

CMC

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Since the pioneering studies of Fleckenstein and co-workers, L-Type Calcium Channel (LTCC) blockers have attracted large interest due to their effectiveness in treating several cardiovascular diseases. Medicinal chemists achieved high potency and tissue selectivity by decorating the 1-4-DHP nucleus, the most studied scaffold among LTCC blockers. Nowadays it is clear that the 1,4-DHP nucleus is a privileged scaffold since, when appropriately substituted, it can selectively modulate diverse receptors, channels and enzymes. Therefore, the 1,4-DHP scaffold could be used to treat various diseases by a single-ligand multi-target approach. In this review, we describe the structure-activity relationships of 1,4-DHPs at ion channels, G-protein coupled receptors, and outline the potential for future therapeutic applications.

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Section: Activity Of 14-dhps On N-type Calcium Channelsmentioning

confidence: 99%

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story so Far And Perspectives (Part 1): Action in Ion Channels and GPCRs

Ioan¹,

Carosati²,

Micucci³

et al. 2011

CMC

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“…[28] Preparation of homologue 6, which bears a free carboxylic group at position 5, was achieved through the mild saponification of the corresponding 2-cyanoethyl ester Biginelli product 5. [29,30] Condensation of DHPMs with chloroacetyl chloride and the appropriate benzaldehydes in the presence of sodium acetate in acetic acid/acetic anhydride medium at reflux provided the final thiazolopyrimidines 35-59 and 67-74 as Z isomers, as previously described (Scheme 1). [31][32][33][34] To avoid esterification of the phenolic functions introduced as R 4 and/or R 3 moieties, the…”

Section: Resultsmentioning

confidence: 99%

Development of Novel Thiazolopyrimidines as CDC25B Phosphatase Inhibitors

et al. 2009

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The development of CDC25 phosphatase inhibitors is an interesting approach toward new antitumor agents, as CDC25 play key roles in cell-cycle regulation and are overexpressed in numerous cancers. We previously reported a novel compound belonging to the thiazolopyrimidine family that inhibits CDC25 activity with an IC(50) value of 13 microM and displays cytotoxic properties against HeLa cells. Structural modifications were subsequently conducted on this new pharmacophore which led to a library of 45 thiazolopyrimidines. Regarding the in vitro effects, 14 compounds inhibit CDC25B with IC(50)<20 microM, with the most efficient inhibitor 44 improving the potency to 4.5 microM. Steady-state kinetics were performed and showed a mixed inhibition pattern for all tested compounds. Furthermore, 44 was able to revert the bypass of genotoxicity-induced G(2) arrest upon CDC25B overexpression, indicating that this compound targets the dual-specificity phosphatase in cultured cells. Finally, the cytotoxic activities of the compounds were determined against two human cancer cell lines. The results indicate that the prostatic LNCaP cell line is more sensitive to these derivatives than the pancreatic adenocarcinoma MiaPaCa-2 line. With its interesting enzymatic and cellular properties, compound 44 appears to be a promising CDC25B inhibitor for further development.

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“…Furthermore, the block of NE release from sympathetic nerve endings in which N-type Ca 2+ channel play a dominant role in the release of neurotransmitters may prevent the emotional stress (Hirning et al 1988;Clasbrummel et al 1989). 1, 4-Dihydropyridine derived long acting calcium channel blockers may have dual effects on both L-and N-type Ca 2+ channels such as cilnidipine, a typical L-and N-type Ca 2+ channel blocker (Yamamoto et al 2006). It is important to assess the effects of Land N-type Ca 2+ channel blocking drugs accurately; however, there has been no method available that can simultaneously assess effects of each channel blocking drugs.…”

Section: Preparation Of Isolated Blood-perfused Papillary Muscle Prepmentioning

confidence: 99%

Assessment of the Effects of L- and N-Type Ca2+ Channel Blocking Drugs Using Canine Blood-Perfused Papillary Muscle Preparations

Daitoku

Seya

Furukawa

et al. 2007

Tohoku J. Exp. Med.

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It is important to accurately and conveniently assess the effects of L-and N-type Ca 2+ channel blocking drugs, which are commonly used for treatment of hypertension, but no method is available to simultaneously assess the effects of them in the same preparation. We have therefore designed an ex vivo method to measure the changes in contractile response of anterior papillary muscle of right ventricle and myocardial interstitial norepinephrine (NE) level using canine blood-perfused papillary muscle preparations. Papillary muscle-developed tension (PMDT) induced by an electronic stimulator was measured with force transducer. Myocardial interstitial NE effluent was collected by microdialysis fiber, which was implanted at the base of the papillary muscle, and measured with high performance liquid chromatography. Cilnidipine, a typical L-and N-type Ca 2+ channel blocker, was used to prove the efficiency of this method. First, to assess the effects of drugs on L-type Ca 2+ channel, the changes in basal PMDT were measured. Cilnidipine and nicardipine, a selective L-type Ca 2+ channel blocker, but not omega-conotoxin GVIA (ω -CTX), a selective N-type Ca 2+ channel blocking peptide, decreased basal PMDT dose-dependently. Second, to assess the effects of drugs on N-type Ca 2+ channel, the changes in PMDT and myocardial interstitial NE level by intracardiac sympathetic ganglion stimulation were measured. Cilnidipine and ω -CTX, but not nicardipine, dose-dependently reduced sympathomimetic increases in PMDT and myocardial interstitial NE level. These results indicate that our method is efficient to assess the effects of various L-and N-type Ca 2+ channel blocking drugs in the same papillary muscle preparation.L-type calcium channel; N-type calcium channel; microdialysis; myocardial interstitial norepinephrine; developed tension

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Structure–activity relationship study of 1,4-dihydropyridine derivatives blocking N-type calcium channels

Cited by 34 publications

References 24 publications

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story so Far And Perspectives (Part 1): Action in Ion Channels and GPCRs

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story so Far And Perspectives (Part 1): Action in Ion Channels and GPCRs

Development of Novel Thiazolopyrimidines as CDC25B Phosphatase Inhibitors

Assessment of the Effects of L- and N-Type Ca2+ Channel Blocking Drugs Using Canine Blood-Perfused Papillary Muscle Preparations

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