RBx 6198: A novel α1-adrenoceptor antagonist for the treatment of benign prostatic hyperplasia

Nanda, Kamna; Naruganahalli, Krishna S.; Gupta, Suman; Malhotra, Shivani; Tiwari, Atul; Hegde, Laxminarayan G.; Jain, Sanjay; Sinha, Neelima; Gupta, Jung B.; Chugh, Anita; Anand, Nitya; Ray, Abhijit

doi:10.1016/j.ejphar.2009.02.026

Cited by 11 publications

(3 citation statements)

References 23 publications

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“…There is still interest in a 1A /a 1D -antagonists (Chiu et al 2007;Liu et al 2009;Nanda et al 2009), since some investigators feel that this profile offers a superior efficacy versus side-effect profile compared to the non-subtype-selective compounds. It has been proposed that bladder a 1D -adrenoceptors may be upregulated as a consequence of the chronic obstruction by the enlarged prostate and that blockade of this receptor subtype may reduce bladder hyperactivity (González Enguita et al 2003;Schwinn and Roehrborn 2008).…”

Section: Use Of Animal Models To Identify New a 1 -Adrenoceptor Antagmentioning

confidence: 97%

Animal Models for Benign Prostatic Hyperplasia

Hieble

2011

Urinary Tract

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Although the etiology of benign prostatic hyperplasia (BPH) is unknown, various animal models have been used for several decades to identify potential therapeutic approaches. These models can be divided into those measuring smooth muscle tone and those measuring cellular proliferation. Animal models have played an important role in the development of the two drug classes currently approved for the treatment of BPH: the α-adrenoceptor antagonists and the steroid 5-α-reductase inhibitors. However, models measuring prostatic tone have not been particularly useful in the identification of new α-adrenoceptor antagonists having advantages over currently available drugs, and it is not certain that reduction of prostatic smooth muscle tone is responsible for the relief of BPH symptoms. A further limitation with BPH models is that prostatic hyperplasia similar to the human condition does not occur spontaneously or cannot be induced in any suitable animal species. The identification of a more useful BPH model is focused on cellular mechanisms of prostatic growth, looking similarities between humans and experimental animals.

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Section: Use Of Animal Models To Identify New a 1 -Adrenoceptor Antagmentioning

confidence: 97%

Animal Models for Benign Prostatic Hyperplasia

Hieble

2011

Urinary Tract

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“…Based on their distinct pharmacological properties, α 1 -ARs are classified into three subtypes, namely α 1A , α 1B and α 1D . 2,3 In the last years, subtype-selective α 1 -AR antagonists were deemed to be attractive drug candidates for the treatment of benign prostatic hyperplasia (BPH) which is a common condition that severely impairs patient's health in aging males. 4,5 Arylpiperazine derivatives exhibited extensive bioactivities including the management of BPH progression.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, crystal structure, biological evaluation and molecular docking studies of carbazole-arylpiperazine derivatives

Xü

Huang

Shao

et al. 2016

Bioorganic & Medicinal Chemistry

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Subtype-selective α-adrenoceptor (AR) antagonists display optimum therapeutic efficacies for the treatment of benign prostatic hyperplasia (BPH). In this study, we designed and synthesized novel carbazole-arylpiperazines derivatives (1 and 2) on the basis of the proposed pharmacophore model for α-AR antagonists. Structural properties were investigated using single-crystal X-ray diffraction analysis. Comparison of crystal structures with ligand-based pharmacophore models revealed that the two agents may possess antagonistic effects on α subtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on α-AR (pA 7.13) with a poor selectivity for α and α subtypes. Compound 1 exhibited enhanced antagonistic effect on α subtype (pA 7.06) and excellent selectivity for α over α (α/α ratio=79.4). To illustrate the relationship between antagonistic activity and chemical structure, molecular docking studies were performed using the homology models of α receptors. Binding mechanism indicated that small hydrophobic substituents attached to the arylpiperazine moiety were essential for rational design of α-selective antagonists.

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“…Although in vitro binding studies and functional experiments have been used to assess compounds’ pharmacological profiles at α 1 -ARs, HTS-compatible methods for subtype-selective α 1 -ARs agonists/antagonists are still lacking [10,11]. Reporter gene systems have been used to detect the activation of specific signaling cascades, followed by monitoring of the reporter protein expression by its enzymatic activity, which is linked to a variety of colorimetric, fluorescent, or luminescent read-outs.…”

Section: Introductionmentioning

confidence: 99%

Identification of Two Novel α1-AR Agonists Using a High-Throughput Screening Model

Chen

et al. 2014

Molecules

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α 1 -Adrenoceptors (ARs; 1A, 1B, and 1D) have been determined to perform different prominent functions in the physiological responses of the sympathetic nervous system. A high-throughput screening assay (HTS) was set up to detect α 1 -AR subtype-selective agonists by a dual-luciferase reporter assay in HEK293 cells. Using the HTS assay, two novel compounds, CHE3 and CHK3, were discovered as α 1 -ARs agonists in α 1 -ARs expressed in HEK293 cells. These compounds also showed moderate/weak anti-proliferative activities against tested cancer cell lines. The HTS assay proposed in this study represents a potential method for discovering more α 1 -AR subtype-selective ligands.

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RBx 6198: A novel α1-adrenoceptor antagonist for the treatment of benign prostatic hyperplasia

Cited by 11 publications

References 23 publications

Animal Models for Benign Prostatic Hyperplasia

Animal Models for Benign Prostatic Hyperplasia

Design, synthesis, crystal structure, biological evaluation and molecular docking studies of carbazole-arylpiperazine derivatives

Identification of Two Novel α1-AR Agonists Using a High-Throughput Screening Model

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