Lead optimization of 5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxyhexanamides to reduce a cardiac safety issue: Discovery of DS-8108b, an orally active renin inhibitor

Nakamura, Yuji; Fujimoto, Teppei; Ogawa, Yasuyuki; Namiki, Hidenori; Suzuki, Sayaka; Asano, Masayoshi; Sugita, Chie; Mochizuki, Akiyoshi; Miyazaki, Shojiro; Tamaki, Koreaki; Nagai, Yoko; Inoue, Shinichi; Nagayama, Takahiro; Kato, Mikio; Chiba, Katsuyoshi; Takasuna, Kiyoshi; Nishi, Takahide

doi:10.1016/j.bmc.2013.03.022

Cited by 10 publications

(2 citation statements)

References 27 publications

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“…Moreover, anti-inflammatory activity was reported in several adamantane-containing molecules [ 19 , 20 , 21 , 22 , 35 , 36 , 37 , 38 ]. Arterolane (XV) [ 39 ], adaprolol (XVI) [ 40 ] and DS-8108b (XVII) [ 41 ] are recently developed adamantane-containing drugs for the treatment of malaria, glaucoma and hypertension, respectively.…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial and Hypoglycemic Activities of Novel N-Mannich Bases Derived from 5-(1-Adamantyl)-4-substituted-1,2,4-triazoline-3-thiones

Al‐Abdullah

Al-Tuwaijri

Hassan

et al. 2014

IJMS

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The reaction of 5-(1-adamantyl)-4-ethyl or allyl-1,2,4-triazoline-3-thione with formaldehyde solution and various 1-substituted piperazines yielded the corresponding N-Mannich bases. The newly synthesized N-Mannich bases were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Six compounds showed potent antibacterial activity against one or more of the tested microorganisms, while two compounds exhibited moderate activity against the tested Gram-positive bacteria. None of the newly synthesized compounds were proved to possess marked activity against Candida albicans. The oral hypoglycemic activity of six compounds was determined in streptozotocin (STZ)-induced diabetic rats. Four compounds produced significant strong dose-dependent reduction of serum glucose levels, compared to gliclazide at 10 mg/kg dose level (potency ratio > 75%).

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Section: Introductionmentioning

confidence: 99%

Antimicrobial and Hypoglycemic Activities of Novel N-Mannich Bases Derived from 5-(1-Adamantyl)-4-substituted-1,2,4-triazoline-3-thiones

Al‐Abdullah

Al-Tuwaijri

Hassan

et al. 2014

IJMS

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“…On the other hand, the isolation of the free γ-hydroxycarboxylic acid after acidification of the potassium salt and subsequent extraction is reported, too [18]. Commonly, the γ-hydroxycarboxylate is protonated in situ [19] or the crude mixture after acidification of the γ-hydroxycarboxylate is directly used for further transformations [20, 21]. An interesting aspect is the potential stabilization of the γ-hydroxycarboxylic acid by basic moieties of the molecular structure and formation of a zwitterionic species [22].…”

Section: Resultsmentioning

confidence: 99%

Synthesis of γ-hydroxy-α-(arylmethyl)carboxylic acids from lactones: pathway to a structural motif derived from lactic acid and amino acid analogs?

et al. 2019

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Objective A synthetic pathway to γ-hydroxy-α-(arylmethyl)carboxylic acids starting from α-angelica lactone and γ-butyrolactone was investigated. These γ-hydroxycarboxylic acids resemble structural motifs of lactic acid and amino acids. The possibility of cocondensation with lactic acid towards functionalized poly(lactic acid)s was analyzed. Results The functional γ-hydroxycarboxylates sodium 4-hydroxy-2-(( N -methylpyrazol-4-yl)methyl)pentanoate and sodium 4-hydroxy-2-(phenylmethyl)butanoate (2-benzyl-4-hydroxybutanoate) were synthesized in good yields as a proof of concept for the proposed reaction pathway. Additionally, sodium ( E )-2-(( N -methylpyrazol-4-yl)methylene)-4-oxopentanoate presenting an interesting structural motif was isolated. All products have been fully characterized by mass spectrometry, IR spectroscopy and 2D nuclear magnetic resonance (NMR) techniques. In contrast to the carboxylate anions, the corresponding carboxylic acids obtained after acidification were found to be unstable. The instability was analyzed by NMR experiments. With the help of diffusion ordered NMR spectroscopy, the cocondensation with lactic acid was elucidated. The reaction products were characterized as oligomers of pure lactic acid, while intramolecular condensation of the γ-hydroxycarboxylic acids prevents cocondensation with lactide. Electronic supplementary material The online version of this article (10.1186/s13104-019-4232-1) contains supplementary material, which is available to authorized users.

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Synthesis and optimization of novel (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as orally active renin inhibitors

Mori

Ogawa

Mochizuki

et al. 2013

Bioorganic & Medicinal Chemistry

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Lead optimization of 5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxyhexanamides to reduce a cardiac safety issue: Discovery of DS-8108b, an orally active renin inhibitor

Cited by 10 publications

References 27 publications

Antimicrobial and Hypoglycemic Activities of Novel N-Mannich Bases Derived from 5-(1-Adamantyl)-4-substituted-1,2,4-triazoline-3-thiones

Antimicrobial and Hypoglycemic Activities of Novel N-Mannich Bases Derived from 5-(1-Adamantyl)-4-substituted-1,2,4-triazoline-3-thiones

Synthesis of γ-hydroxy-α-(arylmethyl)carboxylic acids from lactones: pathway to a structural motif derived from lactic acid and amino acid analogs?

Synthesis and optimization of novel (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as orally active renin inhibitors

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