Discovery of benzimidazole derivatives as orally active renin inhibitors: Optimization of 3,5-disubstituted piperidine to improve pharmacokinetic profile

Tokuhara, Hidekazu; Imaeda, Yasuhiro; Fukase, Yoshiyuki; Iwanaga, Koichi; Taya, Naohiro; Watanabe, Kei; Kanagawa, Ray; Matsuda, Keisuke; Kajimoto, Yumiko; Kusumoto, Keiji; Kondo, Mitsuyo; Snell, G.; Behnke, Craig A.; Kuroita, Takanobu

doi:10.1016/j.bmc.2018.04.051

Cited by 7 publications

(3 citation statements)

References 41 publications

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“…However, as others before us 36,37 , we encountered difficulties controlling the apparent substituent dependent outcome of the reduction of the nitro group. Moreover, the isolation of the resulting amine, under the given reaction conditions, proved complicated.…”

Section: Synthesis Of Target Compoundsmentioning

confidence: 88%

Structural Determinants for the Mode of Action of the Imidazopyridine DS2 at d-containing g-Aminobutyric Acid Type A (GABAA) Receptors

Frølund

Rostrup²,

Falk-Petersen³

et al. 2020

Preprint

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<div>A SAR study of the delta-selective positive modulators DS2 was performed to assist the quest for the binding site. The modulatory effect was measured using a fluorometric inaging plate reader (FLIPR) membrane potential (FMP) functional assay. Specific positions in the structural scaffold of DS2 was found to severly affect the pharmacological profile. <br></div><div>Analogs superior to DS2 were identified displaying higher potency and selectivity for the alfa4beta1delta over alfa4beta1gamma.<br></div><br>

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Section: Synthesis Of Target Compoundsmentioning

confidence: 88%

Structural Determinants for the Mode of Action of the Imidazopyridine DS2 at d-containing g-Aminobutyric Acid Type A (GABAA) Receptors

Frølund

Rostrup²,

Falk-Petersen³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…However, as others before us, , we encountered difficulties in controlling the apparent substituent-dependent outcome of the reduction of the nitro group. Moreover, the isolation of the resulting amine, under the given reaction conditions, proved complicated.…”

Section: Resultsmentioning

confidence: 99%

Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors

Rostrup

Falk-Petersen

et al. 2021

J. Med. Chem.

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Despite the therapeutic relevance of δ-containing γ-aminobutyric acid type A receptors (GABAARs) and the need for δ-selective compounds, the structural determinants for the mode and molecular site of action of δ-selective positive allosteric modulator imidazo[1,2-a]pyridine DS2 remain elusive. To guide the quest for insight, we synthesized a series of DS2 analogues guided by a structural receptor model. Using a fluorescence-based fluorometric imaging plate reader membrane potential assay, we found that the δ-selectivity and the pharmacological profile are severely affected by substituents in the 5-position of the imidazopyridine core scaffold. Interestingly, the 5-methyl, 5-bromo, and 5-chloro DS2 analogues, 30, 35, and 36, were shown to be superior to DS2 at α4β1δ as mid-high nanomolar potency δ-selective allosteric modulators, displaying 6–16 times higher potency than DS2. Of these, 30 also displayed at least 60-fold selectivity for α4β1δ over α4β1γ2 receptor subtypes representing a potential tool for the selective characterization of δ-containing GABAARs in general.

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“…The above method has found application in medicinal chemistry [ 75 , 76 ]. In 2015, Gong and co-workers obtained a number of imidazolones 152, which were then used in the synthesis of a series of potential c-Met kinase inhibitors 153 ( Scheme 34 ) [ 75 ].…”

Section: Azoles With Two Heteroatomsmentioning

confidence: 99%

Diazocarbonyl and Related Compounds in the Synthesis of Azoles

et al. 2021

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Diazocarbonyl compounds have found numerous applications in many areas of chemistry. Among the most developed fields of diazo chemistry is the preparation of azoles from diazo compounds. This approach represents a useful alternative to more conventional methods of the synthesis of azoles. A comprehensive review on the preparation of various azoles (oxazoles, thiazoles, imidazoles, pyrazoles, triazoles, and tetrazoles) from diazocarbonyl and related compounds is presented for the first time along with discussion of advantages and disadvantages of «diazo» approaches to azoles.

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Discovery of benzimidazole derivatives as orally active renin inhibitors: Optimization of 3,5-disubstituted piperidine to improve pharmacokinetic profile

Cited by 7 publications

References 41 publications

Structural Determinants for the Mode of Action of the Imidazopyridine DS2 at d-containing g-Aminobutyric Acid Type A (GABAA) Receptors

Structural Determinants for the Mode of Action of the Imidazopyridine DS2 at d-containing g-Aminobutyric Acid Type A (GABAA) Receptors

Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors

Diazocarbonyl and Related Compounds in the Synthesis of Azoles

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