Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach

Matsufuji, Tetsuyoshi; Shimada, Kousei; Kobayashi, Shozo; Ichikawa, Masanori; Kawamura, Asuka; Fujimoto, Teppei; Arita, Tsuyoshi; Hara, Toshimasa; Konishi, Masahiro; Abe-Ohya, Rie; Izumi, Masanori; Sogawa, Yoshitaka; Nagai, Yoko; Yoshida, Kazuhiro; Abe, Yasuyuki; Kimura, Takako; Takahashi, Hisashi

doi:10.1016/j.bmc.2014.11.018

Cited by 17 publications

(23 citation statements)

References 39 publications

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“…These results[25] demonstrate the peptide and MK-5046’s activation of hBRS were not always concordant raising the possibility they could lead to different cellular responses. Investigators at Daiichi Sankyo Co. Ltd[76,77] recently report a series of chiral diazepine analogues with low brain penetration, which function as high affinity BRS-3 agonists. Results assessing affinity of three of these chiral diazepine analogues (9G, 9D, compound 17c) are shown in Table 2 demonstrating that they function as selective BRS-3 ligands[30,76,77].…”

Section: Brs-3 and The Mammalian Bnr Family (Table 1)mentioning

confidence: 99%

“…Investigators at Daiichi Sankyo Co. Ltd[76,77] recently report a series of chiral diazepine analogues with low brain penetration, which function as high affinity BRS-3 agonists. Results assessing affinity of three of these chiral diazepine analogues (9G, 9D, compound 17c) are shown in Table 2 demonstrating that they function as selective BRS-3 ligands[30,76,77]. As will be discussed in more detail in the next section, it is proposed that because of their low brain penetrance, they may lack side-effects seen in trials with MK-5046, and be potentially useful anti-obesity agents[76,77].…”

Section: Brs-3 and The Mammalian Bnr Family (Table 1)mentioning

confidence: 99%

“…Most of the BRS-3 selective agonists discussed above including MK-5046 and MK-7725, are brain penetrant[75–77,81]. Because of the possibility that the cardiovascular side-effects seen with MK-5046[75,78] could be due to brain penetrance and activation of CNS sympathetic cascades, low brain penetrant BRS-3 selective agonists were developed(ie.19d,19g, compound 17c,Table 2)[76,77]. A novel chiral diazepine analogue with a labile carboxylic ester with antedrug functionality introduced onto the terminal position to yield only a peripheral acting compound, compound 17c(Table 2)[76] was selected and tested on food intake in B6 mice.…”

Section: Brs-3 In Obesity; Energy and Glucose Homeostasis And Diabmentioning

confidence: 99%

“…The recent development of peripherally acting BRS-3 agonists without CNS penetration(compounds 9D,G,cmpd 17c, Table 2, Fig. 1)[76,77], and the demonstration that one of these, compound 17c, (Fig. 1, Table 2) can cause weight loss in animals[76], suggests that the peripheral action of BRS-3 may also be therapeutic, without a central component.…”

Section: Expert Opinionmentioning

confidence: 99%

“…1)[76,77], and the demonstration that one of these, compound 17c, (Fig. 1, Table 2) can cause weight loss in animals[76], suggests that the peripheral action of BRS-3 may also be therapeutic, without a central component. One would expect that the peripheral effects on glucose and insulin homeostasis seen with the central acting BRS-3 agonists (Table 3), would also be seen with the peripheral acting agonists, but as, of now, this has not been studied.…”

Section: Expert Opinionmentioning

confidence: 99%

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Bombesin receptor subtype 3 as a potential target for obesity and diabetes

González

Moreno

Jensen

2015

Expert Opinion on Therapeutic Targets

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Summary Introduction Diabetes mellitus and obesity are important health issues; increasing in prevalence, both in the US and globally. There are only limited pharmacological treatments, and although bariatric surgery is effective, new effective pharmacologic treatments would be of great value. This review covers one area of increasing interest that could yield new novel treatments of obesity/diabetes mellitus. It involves recognition of the central role the G-protein-coupled receptor, bombesin receptor subtype 3(BRS-3) plays in energy/glucose metabolism. Areas covered Since the initial observation that BRS-3-knockout mice develop obesity, hypertension, impaired glucose-metabolism, and hyperphagia, there has been numerous studies of the mechanisms involved and the development of selective BRS-3-agonists/ antagonists which have marked effects on body weight, feeding, and glucose/insulin homeostasis. In this review each of these areas will be briefly reviewed. Expert opinion BRS-3 plays an important role in glucose/energy homeostasis. The development of potent, selective BRS-3 agonists demonstrates promise as a novel approach to treat obesity/diabetic states. One important question that needs to be addressed is whether BRS-3 agonists need to be centrally-acting. This is particular important in light of recent animal and human studies that report transient cardiovascular side-effects with centrally acting oral BRS-agonists.

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Section: Brs-3 and The Mammalian Bnr Family (Table 1)mentioning

confidence: 99%

Section: Brs-3 and The Mammalian Bnr Family (Table 1)mentioning

confidence: 99%

Section: Brs-3 In Obesity; Energy and Glucose Homeostasis And Diabmentioning

confidence: 99%

Section: Expert Opinionmentioning

confidence: 99%

Section: Expert Opinionmentioning

confidence: 99%

See 3 more Smart Citations

Bombesin receptor subtype 3 as a potential target for obesity and diabetes

González

Moreno

Jensen

2015

Expert Opinion on Therapeutic Targets

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Bombesin receptor subtype‐3‐expressing neurons regulate energy homeostasis through a novel neuronal pathway in the hypothalamus

et al. 2017

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ObjectivesBombesin receptor subtype‐3 (BRS‐3) has been suggested to play a potential role in energy homeostasis. However, the physiological mechanism of BRS‐3 on energy homeostasis remains unknown. Thus, we investigated the BRS‐3‐mediated neuronal pathway involved in food intake and energy expenditure.Materials and MethodsExpression of BRS‐3 in the rat brain was histologically examined. The BRS‐3 neurons activated by refeeding‐induced satiety or a BRS‐3 agonist were identified by c‐Fos immunostaining. We also analyzed expression changes in feeding‐relating peptides in the brain of fasted rats administered with the BRS‐3 agonist.ResultsIn the paraventricular hypothalamic nucleus (PVH), dorsomedial hypothalamic nucleus (DMH), and medial preoptic area (MPA), strong c‐Fos induction was observed in the BRS‐3 neurons especially in PVH after refeeding. However, the BRS‐3 neurons in the PVH did not express feeding‐regulating peptides, while the BRS‐3 agonist administration induced c‐Fos expression in the DMH and MPA, which were not refeeding‐sensitive, as well as in the PVH. The BRS‐3 agonist administration changed the Pomc and Cart mRNA level in several brain regions of fasted rats.ConclusionThese results suggest that BRS‐3 neurons in the PVH are a novel functional subdivision in the PVH that regulates feeding behavior. As the MPA and DMH are reportedly involved in thermoregulation and energy metabolism, the BRS‐3 neurons in the MPA/DMH might mediate the energy expenditure control. POMC and CART may contribute to BRS‐3 neuron‐mediated energy homeostasis regulation. In summary, BRS‐3‐expressing neurons could regulate energy homeostasis through a novel neuronal pathway.

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Synthesis of Benzodiazepines Through Ring Opening/Ring Closure of Benzimidazole Salts

Sheng

Shi

et al. 2020

Chemistry A European J

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Pyrido‐benzodiazepine derivatives are undoubtedly one of the most important structural motifs in the marketed drugs and the drug candidates. Commonly synthetic methods for construction of the benzodiazepine ring derivatives are based on the condensation reactions of two highly functionalized synthons. The development of synthesis for these compounds, however, is hampered by the regioselectivity and atom economy. In this work, a one‐step synthesis of pyrido‐benzodiazepine backbones and its analogues is achieved through continuous ring‐opening hydrolysis of benzimidazole salts and intramolecular C−H bond activation. The reaction mechanism is explored by control experiments and density functional theory (DFT) calculations.

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Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach

Cited by 17 publications

References 39 publications

Bombesin receptor subtype 3 as a potential target for obesity and diabetes

Bombesin receptor subtype 3 as a potential target for obesity and diabetes

Bombesin receptor subtype‐3‐expressing neurons regulate energy homeostasis through a novel neuronal pathway in the hypothalamus

Synthesis of Benzodiazepines Through Ring Opening/Ring Closure of Benzimidazole Salts

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