Synthesis and structure–activity relationships of amide derivatives of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetic acid as selective arginine vasopressin V2 receptor agonists

Tsukamoto, Issei; Koshio, Hiroyuki; Kuramochi, Takahiro; Saitoh, Chikashi; Yanai-Inamura, Hiroko; Kitada-Nozawa, Chika; Yamamoto, Eisaku; Yatsu, Takeyuki; Shimada, Yoshiaki; Sakamoto, Shuichi; Tsukamoto, Shin‐ichi

doi:10.1016/j.bmc.2009.03.001

Cited by 15 publications

(12 citation statements)

References 23 publications

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“…Similar effect is observed in a novel series of arginine vasopressin V2 receptor agonists. The compound with carboxygroup does not inhibit CYP3A4 while others do [47]. Introduction of a methyl ester shows positive impact on CYP3A4 inhibition both analyzing experimental data and predictions of our model (p in the range from 0.34 to 0.48 for esters, corresponding Dlogit(p) in the range between 0.18 and 0.77).…”

Section: Resultsmentioning

confidence: 88%

Trainable structure–activity relationship model for virtual screening of CYP3A4 inhibition

Didžiapetris¹,

Dapkūnas

Sazonovas³

et al. 2010

J Comput Aided Mol Des

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A new structure-activity relationship model predicting the probability for a compound to inhibit human cytochrome P450 3A4 has been developed using data for >800 compounds from various literature sources and tested on PubChem screening data. Novel GALAS (Global, Adjusted Locally According to Similarity) modeling methodology has been used, which is a combination of baseline global QSAR model and local similarity based corrections. GALAS modeling method allows forecasting the reliability of prediction thus defining the model applicability domain. For compounds within this domain the statistical results of the final model approach the data consistency between experimental data from literature and PubChem datasets with the overall accuracy of 89%. However, the original model is applicable only for less than a half of PubChem database. Since the similarity correction procedure of GALAS modeling method allows straightforward model training, the possibility to expand the applicability domain has been investigated. Experimental data from PubChem dataset served as an example of in-house high-throughput screening data. The model successfully adapted itself to both data classified using the same and different IC₅₀ threshold compared with the training set. In addition, adjustment of the CYP3A4 inhibition model to compounds with a novel chemical scaffold has been demonstrated. The reported GALAS model is proposed as a useful tool for virtual screening of compounds for possible drug-drug interactions even prior to the actual synthesis.

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Section: Resultsmentioning

confidence: 88%

Trainable structure–activity relationship model for virtual screening of CYP3A4 inhibition

Didžiapetris¹,

Dapkūnas

Sazonovas³

et al. 2010

J Comput Aided Mol Des

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“…35,36 The synthesis of intermediates 6h – n consisted of displacement of one of the bromides of 2,6-dibromopyridine ( 7 ) by refluxing in the appropriate amine. 37,38 …”

Section: Resultsmentioning

confidence: 99%

Diarylureas as Allosteric Modulators of the Cannabinoid CB1 Receptor: Structure–Activity Relationship Studies on 1-(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1)

et al. 2014

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The recent discovery of allosteric modulators of the CB1 receptor including PSNCBAM-1 (4) has generated significant interest in CB1 receptor allosteric modulation. Here in the first SAR study on 4, we have designed and synthesized a series of analogs focusing on modifications at two positions. Pharmacological evaluation in calcium mobilization and binding assays revealed the importance of alkyl substitution at the 2-aminopyridine moiety and electron deficient aromatic groups at the 4-chlorophenyl position for activity at the CB1 receptor, resulting in several analogs with comparable potency to 4. These compounds increased the specific binding of [3H]CP55,940, in agreement with previous reports. Importantly, 4 and two analogs dose-dependently reduced the Emax of the agonist curve in the CB1 calcium mobilization assays, confirming their negative allosteric modulator characteristics. Given the side effects associated with CB1 receptor orthosteric antagonists, negative allosteric modulators provide an alternative approach to modulate the pharmacologically important CB1 receptor.

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“…We note that mono-oxidation of bis-methanol-pyridines to carboxaldehyde can also be achieved with MnO 2 as oxidant [34]. The known 2,6-disubsituted pyridines P3 [35][36][37] and P4 [36][37][38], which we planned to use in the synthesis of tetrazoles, were prepared from P1 (we described its multi-gram synthesis before [12]) by conversion of the carboxaldehyde into the carbonitrile P3 with NH 2 OHÁHCl in DMSO [39], and by oxidation of the pyridine-2-methanol to the carboxaldehyde P4 with SeO 2 (Scheme 3).…”

Section: Resultsmentioning

confidence: 98%

“…The product shows one spot on TLC (silica; ethyl acetate). It is soluble in organic solvents, and it remains soluble even after long storage as a solid (in contrast to the nonsubstituted analog P1 P3: For alternative syntheses, see [35][36][37]. The reaction was performed under nitrogen.…”

Section: Synthesis Of Pyridinesmentioning

confidence: 99%

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Synthesis and spectroscopy of anionic tridentate benzimidazole-pyridine carboxylate and tetrazolate chromophore ligands

Shavaleev

Eliseeva

2015

Inorganica Chimica Acta

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Synthesis and structure–activity relationships of amide derivatives of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetic acid as selective arginine vasopressin V2 receptor agonists

Cited by 15 publications

References 23 publications

Trainable structure–activity relationship model for virtual screening of CYP3A4 inhibition

Trainable structure–activity relationship model for virtual screening of CYP3A4 inhibition

Diarylureas as Allosteric Modulators of the Cannabinoid CB1 Receptor: Structure–Activity Relationship Studies on 1-(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1)

Synthesis and spectroscopy of anionic tridentate benzimidazole-pyridine carboxylate and tetrazolate chromophore ligands

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