Kiwon Chung - Academia.edu (original) (raw)
Papers by Kiwon Chung
L'invention concerne un procede de traitement, de prevention, de suppression, d'inhibitio... more L'invention concerne un procede de traitement, de prevention, de suppression, d'inhibition ou de reduction de l'incidence de l'hyperplasie prostatique benigne chez un sujet mâle, par administration a ce dernier d'un modulateur selectif des recepteurs androgenes (SARM) et/ou d'un de ses analogue, derive, isomere, metabolite, sel acceptable sur le plan pharmaceutique, produit pharmaceutique, hydrate, N-oxyde, ou n'importe quelle combinaison de ceux-ci, de la maniere decrite dans la description. Cette invention concerne egalement un procede de traitement d'un sujet souffrant de perte de cheveux, consistant a administrer au sujet une quantite efficace sur le plan therapeutique d'une enzyme 5-α-reductase de type 1 et/ou d'un inhibiteur de type 2, cet inhibiteur consistant en un modulateur selectif des recepteurs androgenes (SARM) et/ou un de ses analogue, derive, isomere, metabolite, sel acceptable sur le plan pharmaceutique, produit pharmaceutique...
Journal of Pharmacology and Experimental Therapeutics, 2002
The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo p... more The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with K i values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (E max) and dose for half-maximal effect (ED 50) were determined for each The in vivo studies reported herein were supported by a grant from GTx, Inc. (Memphis, TN). In vitro pharmacological evaluation was supported by Grant R01 DK59800-01 from the National Institute of Diabetes and Digestive and Kidney Diseases (to J.T.D. and D.D.M.). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
Bioorganic & Medicinal Chemistry Letters, 2007
The conversion of ribavirin to the monophosphate by adenosine kinase is the rate-limiting step in... more The conversion of ribavirin to the monophosphate by adenosine kinase is the rate-limiting step in activation of this broad spectrum antiviral drug. Variation of the 3-substituents in a series of bioisosteric and homologated 1-b-D D-ribofuranosyl-1,2,4-triazoles has marked effects on activity with the human adenosine kinase, and analysis of computational descriptors and binding models offers insight for the design of novel substrates.
Journal of medicinal chemistry, Jan 12, 2004
A series of nonsteroidal ligands were synthesized as second-generation agonists for the androgen ... more A series of nonsteroidal ligands were synthesized as second-generation agonists for the androgen receptor (AR). These ligands were designed to eliminate metabolic sites identified in one of our first-generation AR agonists, which was inactive in vivo due to its rapid metabolism to inactive constituents. The binding affinity of these compounds was evaluated using AR isolated from rat ventral prostate. These second-generation compounds bound the AR in a high affinity and stereoselective manner, with K(i) values ranging from about 4 to 130 nM. The ability of these ligands to stimulate AR-mediated transcriptional activation was examined in cells transfected with the human AR and a hormone-dependent luciferase reporter gene. Although some compounds were unable to stimulate AR-mediated transcription, several demonstrated activity similar to that of dihydrotestosterone (DHT, an endogenous steroidal ligand for the AR). We also evaluated the in vivo pharmacologic activity of selected compoun...
Endocrinology, 2004
Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both cast... more Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5α-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5α-reductase (Ki, >20 µM) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited prostatic 5α-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH.
Endocrinology, 2005
We recently reported two nonsteroidal androgen receptor (AR) ligands that demonstrate tissueselec... more We recently reported two nonsteroidal androgen receptor (AR) ligands that demonstrate tissueselective pharmacological activity, identifying these S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4nitro-3-trifluoromethyl-phenyl)-propionamide analogs as the first members of a new class of drugs known as selective androgen receptor modulators. The purpose of these studies was to explore additional structure-activity relationships of selective androgen receptor modulators to enhance their AR binding affinity, AR-mediated transcriptional activation, and in vivo pharmacological activity. The AR binding affinity (K i ) of 29 novel synthetic AR ligands was determined by a radioligand competitive binding assay and ranged from 1.0-51 nM. Compounds with electron-withdrawing substituents at the para-and meta-positions of the B-ring demonstrated the highest AR binding affinity. The AR-mediated transcriptional activation was determined using a cotransfection assay in CV-1 cells. Most compounds with two substituents in the B-ring maintained or improved their functional activity in vitro. However, compounds with three halogen substituents exhibited significant regioselectivity. Fifteen compounds were selected to examine their pharmacological activity in castrated rats. In vivo pharmacological activity and selectivity were significantly changed by structural modification in the B-ring. Compounds with halogen groups at the para-and metapositions of the B-ring displayed the highest pharmacological activity. Incorporating substituents at the ortho-position of the B-ring resulted in poor pharmacological activity. In vitro and in vivo agonist activities were partially correlated. In conclusion, novel selective androgen receptor modulators with improved in vivo pharmacological activity can be designed and synthesized based on the structureactivity relationship identified in these studies.
Bioorganic & Medicinal Chemistry, 2005
Synthesis and biological characterization of a series of a-tocopherol analogs with NO-releasing c... more Synthesis and biological characterization of a series of a-tocopherol analogs with NO-releasing capacity are reported. The selected NO-donor moieties were nitrooxy and furoxan. All products were tested for their in vitro NO-releasing capacities, vasodilating properties, and antiplatelet activity. They were also capable of preventing LDL oxidation.
Bioorganic & Medicinal Chemistry Letters, 2007
The conversion of ribavirin to the monophosphate by adenosine kinase is the rate-limiting step in... more The conversion of ribavirin to the monophosphate by adenosine kinase is the rate-limiting step in activation of this broad spectrum antiviral drug. Variation of the 3-substituents in a series of bioisosteric and homologated 1-b-D D-ribofuranosyl-1,2,4-triazoles has marked effects on activity with the human adenosine kinase, and analysis of computational descriptors and binding models offers insight for the design of novel substrates.
L'invention concerne un procede de traitement, de prevention, de suppression, d'inhibitio... more L'invention concerne un procede de traitement, de prevention, de suppression, d'inhibition ou de reduction de l'incidence de l'hyperplasie prostatique benigne chez un sujet mâle, par administration a ce dernier d'un modulateur selectif des recepteurs androgenes (SARM) et/ou d'un de ses analogue, derive, isomere, metabolite, sel acceptable sur le plan pharmaceutique, produit pharmaceutique, hydrate, N-oxyde, ou n'importe quelle combinaison de ceux-ci, de la maniere decrite dans la description. Cette invention concerne egalement un procede de traitement d'un sujet souffrant de perte de cheveux, consistant a administrer au sujet une quantite efficace sur le plan therapeutique d'une enzyme 5-α-reductase de type 1 et/ou d'un inhibiteur de type 2, cet inhibiteur consistant en un modulateur selectif des recepteurs androgenes (SARM) et/ou un de ses analogue, derive, isomere, metabolite, sel acceptable sur le plan pharmaceutique, produit pharmaceutique...
Journal of Pharmacology and Experimental Therapeutics, 2002
The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo p... more The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with K i values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (E max) and dose for half-maximal effect (ED 50) were determined for each The in vivo studies reported herein were supported by a grant from GTx, Inc. (Memphis, TN). In vitro pharmacological evaluation was supported by Grant R01 DK59800-01 from the National Institute of Diabetes and Digestive and Kidney Diseases (to J.T.D. and D.D.M.). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
Bioorganic & Medicinal Chemistry Letters, 2007
The conversion of ribavirin to the monophosphate by adenosine kinase is the rate-limiting step in... more The conversion of ribavirin to the monophosphate by adenosine kinase is the rate-limiting step in activation of this broad spectrum antiviral drug. Variation of the 3-substituents in a series of bioisosteric and homologated 1-b-D D-ribofuranosyl-1,2,4-triazoles has marked effects on activity with the human adenosine kinase, and analysis of computational descriptors and binding models offers insight for the design of novel substrates.
Journal of medicinal chemistry, Jan 12, 2004
A series of nonsteroidal ligands were synthesized as second-generation agonists for the androgen ... more A series of nonsteroidal ligands were synthesized as second-generation agonists for the androgen receptor (AR). These ligands were designed to eliminate metabolic sites identified in one of our first-generation AR agonists, which was inactive in vivo due to its rapid metabolism to inactive constituents. The binding affinity of these compounds was evaluated using AR isolated from rat ventral prostate. These second-generation compounds bound the AR in a high affinity and stereoselective manner, with K(i) values ranging from about 4 to 130 nM. The ability of these ligands to stimulate AR-mediated transcriptional activation was examined in cells transfected with the human AR and a hormone-dependent luciferase reporter gene. Although some compounds were unable to stimulate AR-mediated transcription, several demonstrated activity similar to that of dihydrotestosterone (DHT, an endogenous steroidal ligand for the AR). We also evaluated the in vivo pharmacologic activity of selected compoun...
Endocrinology, 2004
Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both cast... more Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5α-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5α-reductase (Ki, >20 µM) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited prostatic 5α-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH.
Endocrinology, 2005
We recently reported two nonsteroidal androgen receptor (AR) ligands that demonstrate tissueselec... more We recently reported two nonsteroidal androgen receptor (AR) ligands that demonstrate tissueselective pharmacological activity, identifying these S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4nitro-3-trifluoromethyl-phenyl)-propionamide analogs as the first members of a new class of drugs known as selective androgen receptor modulators. The purpose of these studies was to explore additional structure-activity relationships of selective androgen receptor modulators to enhance their AR binding affinity, AR-mediated transcriptional activation, and in vivo pharmacological activity. The AR binding affinity (K i ) of 29 novel synthetic AR ligands was determined by a radioligand competitive binding assay and ranged from 1.0-51 nM. Compounds with electron-withdrawing substituents at the para-and meta-positions of the B-ring demonstrated the highest AR binding affinity. The AR-mediated transcriptional activation was determined using a cotransfection assay in CV-1 cells. Most compounds with two substituents in the B-ring maintained or improved their functional activity in vitro. However, compounds with three halogen substituents exhibited significant regioselectivity. Fifteen compounds were selected to examine their pharmacological activity in castrated rats. In vivo pharmacological activity and selectivity were significantly changed by structural modification in the B-ring. Compounds with halogen groups at the para-and metapositions of the B-ring displayed the highest pharmacological activity. Incorporating substituents at the ortho-position of the B-ring resulted in poor pharmacological activity. In vitro and in vivo agonist activities were partially correlated. In conclusion, novel selective androgen receptor modulators with improved in vivo pharmacological activity can be designed and synthesized based on the structureactivity relationship identified in these studies.
Bioorganic & Medicinal Chemistry, 2005
Synthesis and biological characterization of a series of a-tocopherol analogs with NO-releasing c... more Synthesis and biological characterization of a series of a-tocopherol analogs with NO-releasing capacity are reported. The selected NO-donor moieties were nitrooxy and furoxan. All products were tested for their in vitro NO-releasing capacities, vasodilating properties, and antiplatelet activity. They were also capable of preventing LDL oxidation.
Bioorganic & Medicinal Chemistry Letters, 2007
The conversion of ribavirin to the monophosphate by adenosine kinase is the rate-limiting step in... more The conversion of ribavirin to the monophosphate by adenosine kinase is the rate-limiting step in activation of this broad spectrum antiviral drug. Variation of the 3-substituents in a series of bioisosteric and homologated 1-b-D D-ribofuranosyl-1,2,4-triazoles has marked effects on activity with the human adenosine kinase, and analysis of computational descriptors and binding models offers insight for the design of novel substrates.