Discovery of Tetralin Carboxamide Growth Hormone Secretagogue Receptor Antagonists via Scaffold Manipulation

Zhao, Hongyu; Xin, Zhili; Liu, Gang; Schaefer, Verlyn G.; Falls, Hugh D.; Kaszubska, Wiweka; Collins, Christine A.; Sham, Hing L.

doi:10.1021/jm0491750

Cited by 28 publications

(29 citation statements)

References 21 publications

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“…These substances were quinazolinone derivates [67], ligands based on tri-substituted 1,2,4-triazole structure [68,69], tetralin carboxamide [70,71] isoxazole carboxamide [72], 2,4-diaminopyrimidines [73], oxindole [74], piperazine-bisamide [75] GHSR ligands as well as R-prolinol-derivate agonists [76]. …”

Section: Gpcrs As Targets For Treatment Of Cachexia and Obesitymentioning

confidence: 99%

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

et al. 2012

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The worldwide obesity epidemic is increasing, yet at this time, no long-acting and specific pharmaceutical therapies are available. Peripheral hormonal signals communicate metabolic status to the hypothalamus by activating their corresponding receptors in the arcuate nucleus (ARC). In this brain region, a variety of G protein-coupled receptors (GPCRs) are expressed that are potentially involved in weight regulation, but so far, the detailed function of most hypothalamic GPCRs is only partially understood. An important and underappreciated feature of GPCRs is the capacity for regulation via di- and heterodimerization. Increasing evidence implicates that heterodimerization of GPCRs results in profound functional consequences. Recently, we could demonstrate that interaction of the melanocortin 3 receptor (MC3R) and the growth hormone secretagogue receptor (GHSR)-1a results in a modulation of function in both receptors. Although the physiological role of GPCR-GPCR interaction in the hypothalamus is yet to be elucidated, this concept promises new avenues for investigation and understanding of hypothalamic functions dependent on GPCR signaling. Since GPCRs are important targets for drugs to combat many diseases, identification of heterodimers may be a prerequisite for highly specific drugs. Therefore, a detailed understanding of the mechanisms and their involvement in weight regulation is necessary. Fundamental to this understanding is the interplay of GPCR-GPCR in the hypothalamic nuclei in energy metabolism. In this review, we summarize the current knowledge on melanocortin receptors and GHSR-1a in hypothalamic weight regulation, especially as they pertain to possible drug targets. Furthermore, we include available evidence for the participation and significance of GPCR dimerization.

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Section: Gpcrs As Targets For Treatment Of Cachexia and Obesitymentioning

confidence: 99%

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

et al. 2012

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“…Above model Equations (12)(13)(14)(15)(16) were further subjected to randomization process, where 100 simulations per model were carried out but none of the identified models has shown any chance correlation. Additionally, the above model Equations have been concomitantly validated with the external test set of structurally dissimilar (bearing heteroaryl group at R 3 ) eight compounds listed in Table VIII.…”

Section: Resultsmentioning

confidence: 99%

“…They have shown the test set r 2 values in the range of 0.456 to 0.563. The predictions of the test set compounds obtained with the models (12)(13)(14)(15)(16) and the corresponding predictive r 2 have also been given in the same Table.…”

Section: Resultsmentioning

confidence: 99%

“…The inhibition of ghrelin actions with peptidyl GHS-R antagonists [7,9], ghrelin antibody [10], and antisense oligonucleosides [11] resulted in weight loss and food intake decrease in rodents [7,[9][10][11]. The isoxazole and tetralin carboxamide based GHS-R antagonists [12][13][14][15], displaced 125 I-ghrelin binding and antagonized ghrelin-induced intracellular Ca 2+ flux in functional assay. However, these compounds did not exhibit an effect when tested in in vivo animal models.…”

Section: Introductionmentioning

confidence: 99%

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Modeling of the growth hormone secretagogue receptor antagonistic activity using chemometric tools

Sharma¹,

Sharma²,

Pilania³

et al. 2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The scaffold hopping method has been proved very effective in molecular design, as shown in many review papers. For example, in work conducted at Abbott Laboratories, Zhao et al performed scaffold modification on a screening hit and identified potent and selective growth hormone secretagogue receptor (GHS-R) antagonists [9] . The scaffold of the hit antagonist was changed from a phenylisoxazole ring to a tetralin carboxamide, dramatically improving its binding affinity and other physiochemical properties.…”

Section: Introductionmentioning

confidence: 99%

ScafBank: a public comprehensive Scaffold database to support molecular hopping

et al. 2009

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Aim:The search for molecules whose bioactivities are similar to those of given compounds or to optimize the initial lead compounds from high throughput screening has attracted increasing interest in recent years. Our goal is to provide a publically searchable database of scaffolds out from a large collection of existing chemical molecules. Results: Although a number of in silico methods have emerged to facilitate this process, which has become known as "scaffold hopping" or "molecular hopping", there is an urgent need for a database system to provide such valuable data in the drug design field. Here we have systematically analyzed a collection of commercially available small molecule databases and a bioactive compound database to identify unique scaffolds and we have built apublically searchable database. The analysis of approximately 4 800 000 of these compounds identified 241 824 unique scaffolds, which are stored in a relational database (http://202.127.30.184:8080/db.html). Each entry in the database is associated with a molecular occurrence and includes its distribution of molecular properties, such as molecular weight, logP, hydrogen bond acceptor number, hydrogen bond donor number, rotatable bond number and ring number. More importantly, for scaffolds derived from the bioactive compounds database, it also contains the original compounds and their target information. Conclusion: This Web-based database system could help researchers in the fields of medicinal and organic chemistry to design novel molecules with properties similar to the original compounds, but built on novel scaffolds.

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Discovery of Tetralin Carboxamide Growth Hormone Secretagogue Receptor Antagonists via Scaffold Manipulation

Cited by 28 publications

References 21 publications

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

Modeling of the growth hormone secretagogue receptor antagonistic activity using chemometric tools

ScafBank: a public comprehensive Scaffold database to support molecular hopping

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