Promising core structure for nuclear receptor ligands: design and synthesis of novel estrogen receptor ligands based on diphenylamine skeleton

Novel diphenylamine-type estrogen receptor ligands were designed and synthesized, and their biological activities were evaluated by means of binding assays for estrogen receptor-alpha and -beta and cell proliferation assay using MCF-7 cells. Compounds 4f, 11b, 12c, and 8 showed moderate estrogenic activities. We propose that the diphenylamine skeleton may be a privileged structure for various nuclear receptor ligands, including RAR, RXR, and AR ligands.     

m-Carborane bisphenol structure as a pharmacophore for selective estrogen receptor modulators

A series of m-carborane derivatives was prepared based upon the structures of antiestrogenic drugs and their activities were evaluated by estrogen receptor alpha (ERalpha) binding assay and transactivation assay using human breast cancer cell line, MCF-7 cells. The m-carborane bisphenol 5 exhibited about a thousand times more potent ER agonistic activity than the o-carborane bisphenol 11. The m-carborane bisphenol structure appears to be a favorable hydrophobic pharmacophore for the development of novel selective estrogen receptor modulators (SERMs).     

Discovery of indole-containing tetracycles as a new scaffold for androgen receptor ligands

A novel series of tetracyclic indoles have been designed, synthesized and evaluated as androgen receptor (AR) ligands. Studies of structure-activity relationships (SARs) were investigated, which led to some compounds in this series as strong binders to androgen receptors.     

Modulation of human neutrophil activity by adenosine modified with a carborane pharmacophore

An impact of adenosine modification with electroneutral, lipophilic 1,12-dicarba-closo-dodecaborane or electronegative 7,8-dicarba-nido-undecaborane boron cluster at the 6-N, 2′-C and 2-C positions on human neutrophil oxidative burst, neutrophil adherence to fibronectin and protein kinase C activity was studied. Modification of adenosine with 1,12-dicarba-closo-dodecaborane, but not 7,8-dicarba-nido-undecaborane, changes the function of adenosine from an inactive to an active state in regulating neutrophil response to PMA stimulation by reducing neutrophils’ reactivity through a mechanism involving the PKC signaling pathway. Our results show that exogenously administered adenosine derivatives can be useful in regulating the oxidative burst of neutrophils in the inflammatory process.     

A new class of androgen receptor antagonists bearing carborane in place of a steroidal skeleton

A new class of androgen receptor antagonists containing dicarba-closo-dodecaborane (carborane) as a hydrophobic skeletal structure is described. The designed molecules bear the characteristic polar components of endogenous agonists, but have a hydrophobic carborane cage instead of the steroidal skeleton. These compounds bind to androgen receptor and show anti-androgenic activity towards androgen-dependent SC-3 cells with almost the same potency as the known anti-androgen hydroxyflutamide.     

Characterisation of TRPM8 as a pharmacophore receptor

Some proteins of the transient receptor potential (TRP) family form temperature sensitive ion channels. One member of the melastatin (M) group, namely TRPM8 is activated by cold and cooling compounds such as menthol and icilin, and its gene is up-regulated in prostate cancer and other malignancies. Here we characterise the effects of the carboxamides WS-12, CPS-113, CPS-369, the carboxylic acid WS-30 and the phosphine oxide WS-148 by Ca2+ imaging experiments and whole-cell patch-clamp recordings on TRPM8 expressing human embryonic kidney (HEK), lymph node prostate cancer (LNCaP) and dorsal root ganglia (DRG) cells. The cooling compounds introduced in this study, show a dose-dependent and reversible activation of TRPM8 with EC50 values in the nM to low microM range. The carboxamide WS-12 is most potent in activating TRPM8. It is selective, since other TRP proteins are not stimulated at muM concentrations and its efficacy with respect to TRPM8 is similar to the one of icilin. In summary, the compounds described in this study represent new tools to dissect TRPM8 functions and may serve as chemical leads for the development of additional TRPM8 agonists and novel antagonists. Such compounds may be beneficial for preventing noxious cold perception. They could also be useful in diagnosis and treatment of most common cancers in which the TRPM8 gene is up-regulated in comparison to the corresponding normal tissue.     

Characterisation of TRPM8 as a pharmacophore receptor

Some proteins of the transient receptor potential (TRP) family form temperature sensitive ion channels. One member of the melastatin (M) group, namely TRPM8 is activated by cold and cooling compounds such as menthol and icilin, and its gene is up-regulated in prostate cancer and other malignancies. Here we characterise the effects of the carboxamides WS-12, CPS-113, CPS-369, the carboxylic acid WS-30 and the phosphine oxide WS-148 by Ca²⁺ imaging experiments and whole-cell patch-clamp recordings on TRPM8 expressing human embryonic kidney (HEK), lymph node prostate cancer (LNCaP) and dorsal root ganglia (DRG) cells. The cooling compounds introduced in this study, show a dose-dependent and reversible activation of TRPM8 with EC₅₀ values in the nM to low μM range. The carboxamide WS-12 is most potent in activating TRPM8. It is selective, since other TRP proteins are not stimulated at μM concentrations and its efficacy with respect to TRPM8 is similar to the one of icilin. In summary, the compounds described in this study represent new tools to dissect TRPM8 functions and may serve as chemical leads for the development of additional TRPM8 agonists and novel antagonists. Such compounds may be beneficial for preventing noxious cold perception. They could also be useful in diagnosis and treatment of most common cancers in which the TRPM8 gene is up-regulated in comparison to the corresponding normal tissue.     

Pyrazolo[1,5-a]pyrimidines as estrogen receptor ligands: defining the orientation of a novel heterocyclic core

We have examined the pyrazolo[1,5-a]pyrimidine scaffold as a novel core structure for estrogen receptor ligands. Attachment of various substituents has helped to define the orientation of this heterocycle in the ligand-binding pocket as one in which a pendant phenol rather than the hydroxylpyrimidine serves as a mimic of the A-ring of estradiol.     

Alpha-methyltryptamine sulfonamide derivatives as novel glucocorticoid receptor ligands

Alpha-methyltryptamine sulfonamides were identified as human glucocorticoid receptor (hGR) ligands in an ultra high throughput screening (UHTS) campaign. Described will be the hit-to-lead activities, including parallel and single point analog synthesis to map the scaffold. Ligands were identified that exhibited 30 nM binding to hGR. The SAR and selectivity of these compounds will be discussed.     

Identification of novel indole based heterocycles as selective estrogen receptor modulator

In the present study, we have designed and synthesized indole derivatives by coalescing the indole nucleus with chromene carbonitrile and dihydropyridine nucleus. Two compounds 5c and 6d were selected from series I and II after sequential combinatorial library generation, docking, absorption, distribution, metabolism and excretion (ADME) filtering, anti-proliferative activity, cytotoxicity, and ER-α competitor assay kit by utilizing estrogen receptor-α (ER-α) dominant T47D BC cells line and PBMCs (Peripheral Blood Mononuclear Cells). Cell imaging experiment suggested that both the compounds successfully cross cellular biomembrane and accumulate in nuclear, cytoplasmic and plasma membrane region. Semiquantitative RT-PCR and Western blotting experiments further supported that both compounds reduced the expression of mRNA and receptor protein of ER-α, thereby preventing downstream transactivation and signaling pathway in T47D cells line. Current findings imply that 5c and 6d represent novel ER-α antagonists and may be used in the development of chemotherapy for the management of BC.     

Discovery of an androgen receptor modulator pharmacophore based on 2-quinolinones

A series of alkylamino-2-quinolinone compounds (3) was discovered as androgen receptor modulators based on an early linear tricyclic quinoline pharmacophore (1). The series demonstrated selective high binding affinity to androgen receptor and potent receptor modulating activities in the cotransfection assays.     

Design of oxobenzimidazoles and oxindoles as novel androgen receptor antagonists

Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR.     

Synthesis and structure-affinity relationships of novel spirocyclic sigma receptor ligands with furopyrazole structure

The synthesis of novel spirocyclic sigma receptor ligands with high affinity is described. The cyclization of the hydroxy acetal 8, which represents a key step in the synthesis of the spirocyclic compounds 3, was supported by theoretical considerations. The affinity of the spirocyclic furopyrazoles 3a-c to the sigma receptors was determined in receptor binding studies with radioligands. The N-benzyl (3b) and N-butyl (3c) derivatives display very high sigma(1) receptor affinity (3b, K(i)=0.50 nM; 3c, K(i)=1.28 nM) and high selectivity toward the sigma(2) receptor and some other receptor systems. Calculation of crucial distances of the spirocyclic furopyrazole derivatives 3b and 3c shows good correlation with the pharmacophore model of Glennon.     

Sulfamoyl benzamides as novel CB2 cannabinoid receptor ligands

Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB₂ receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB₂ receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.     

Serendipitous discovery of novel imidazolopyrazole scaffold as selective androgen receptor modulators

A novel imidazolopyrazole derivative has been fortuitously discovered as potent selective androgen receptor modulator with in vivo efficacy.     

Synthesis of 3-alkyl naphthalenes as novel estrogen receptor ligands

A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ERalpha and ERbeta binding affinity ranging from micromolar to low nanomolar.