The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3- trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators

Juhyun Kim, Di Wu, Jin Hwang Dong, Duane Miller, James T. Dalton

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Abstract

Selective androgen receptor modulators (SARMs) have many potential therapeutic applications, including male hypogonadism, osteoporosis, muscle-wasting diseases, sexual libido, and contraception. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl) -propionamides bearing a four-halogen substituent in the B-ring that displayed in vivo activity were identified in our previous study. Interestingly, in vivo pharmacological activity was not correlated with in vitro androgen receptor (AR) binding affinity. In this study, analysis of the area under the concentration-time curve-response relationship demonstrated that the discrepancy between in vitro and in vivo pharmacological activity of these halogen-substituted SARMs was due to differences in systemic exposure rather than intrinsic pharmacological activity. Studies also suggested that two simple criteria (i.e., Ki < 10 nM and lower in vivo clearance) could be used to identify efficacious and potent SARMs. We tested this hypothesis using a series of four compounds incorporating either a nitro or cyano substituent at the para-position of the A- and B-aromatic rings. The S-3-(4-Nitrophenoxy) and S-3-(4-cyanophenoxy) 2-hydroxy-2-methyl-N-(4-nitro-3-trifluromethylphenyl) propionamides (S-19 and S-20, respectively) and S-3-(4-nitrophenoxy) and S-3-(4-cyanophenoxy) 2-hydroxy-2-methyl-N-(4-cyano-3-trifluromethylphenyl) propionamides (S-21 and S-22, respectively) demonstrated high AR binding affinity, with Ki values ranging from 2.0 to 3.8 nM. Pharmacokinetic studies of selected compounds showed that the in vivo clearance of S-22 was the slowest followed sequentially by S-20, S-21, and S-19. The dose-response relationships for S-22 showed that S-22 exerted efficacious and selective activity in anabolic tissues at dose rates as low as 0.03 mg/day, indicative of the high potency of this compound in anabolic tissue (relative potency 4.41) and its potential for clinical use in androgen deficiency-related disorders.

Original languageEnglish (US)
Pages (from-to)230-239
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume315
Issue number1
DOIs
StatePublished - Oct 1 2005

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Androgen Receptors
Halogens
Pharmacology
Eunuchism
Wasting Syndrome
Libido
Contraception
Androgens
Osteoporosis
Pharmacokinetics
propionamide
Muscles
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3- trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators",
abstract = "Selective androgen receptor modulators (SARMs) have many potential therapeutic applications, including male hypogonadism, osteoporosis, muscle-wasting diseases, sexual libido, and contraception. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl) -propionamides bearing a four-halogen substituent in the B-ring that displayed in vivo activity were identified in our previous study. Interestingly, in vivo pharmacological activity was not correlated with in vitro androgen receptor (AR) binding affinity. In this study, analysis of the area under the concentration-time curve-response relationship demonstrated that the discrepancy between in vitro and in vivo pharmacological activity of these halogen-substituted SARMs was due to differences in systemic exposure rather than intrinsic pharmacological activity. Studies also suggested that two simple criteria (i.e., Ki < 10 nM and lower in vivo clearance) could be used to identify efficacious and potent SARMs. We tested this hypothesis using a series of four compounds incorporating either a nitro or cyano substituent at the para-position of the A- and B-aromatic rings. The S-3-(4-Nitrophenoxy) and S-3-(4-cyanophenoxy) 2-hydroxy-2-methyl-N-(4-nitro-3-trifluromethylphenyl) propionamides (S-19 and S-20, respectively) and S-3-(4-nitrophenoxy) and S-3-(4-cyanophenoxy) 2-hydroxy-2-methyl-N-(4-cyano-3-trifluromethylphenyl) propionamides (S-21 and S-22, respectively) demonstrated high AR binding affinity, with Ki values ranging from 2.0 to 3.8 nM. Pharmacokinetic studies of selected compounds showed that the in vivo clearance of S-22 was the slowest followed sequentially by S-20, S-21, and S-19. The dose-response relationships for S-22 showed that S-22 exerted efficacious and selective activity in anabolic tissues at dose rates as low as 0.03 mg/day, indicative of the high potency of this compound in anabolic tissue (relative potency 4.41) and its potential for clinical use in androgen deficiency-related disorders.",
author = "Juhyun Kim and Di Wu and Dong, {Jin Hwang} and Duane Miller and Dalton, {James T.}",
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T1 - The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3- trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators

AU - Kim, Juhyun

AU - Wu, Di

AU - Dong, Jin Hwang

AU - Miller, Duane

AU - Dalton, James T.

PY - 2005/10/1

Y1 - 2005/10/1

N2 - Selective androgen receptor modulators (SARMs) have many potential therapeutic applications, including male hypogonadism, osteoporosis, muscle-wasting diseases, sexual libido, and contraception. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl) -propionamides bearing a four-halogen substituent in the B-ring that displayed in vivo activity were identified in our previous study. Interestingly, in vivo pharmacological activity was not correlated with in vitro androgen receptor (AR) binding affinity. In this study, analysis of the area under the concentration-time curve-response relationship demonstrated that the discrepancy between in vitro and in vivo pharmacological activity of these halogen-substituted SARMs was due to differences in systemic exposure rather than intrinsic pharmacological activity. Studies also suggested that two simple criteria (i.e., Ki < 10 nM and lower in vivo clearance) could be used to identify efficacious and potent SARMs. We tested this hypothesis using a series of four compounds incorporating either a nitro or cyano substituent at the para-position of the A- and B-aromatic rings. The S-3-(4-Nitrophenoxy) and S-3-(4-cyanophenoxy) 2-hydroxy-2-methyl-N-(4-nitro-3-trifluromethylphenyl) propionamides (S-19 and S-20, respectively) and S-3-(4-nitrophenoxy) and S-3-(4-cyanophenoxy) 2-hydroxy-2-methyl-N-(4-cyano-3-trifluromethylphenyl) propionamides (S-21 and S-22, respectively) demonstrated high AR binding affinity, with Ki values ranging from 2.0 to 3.8 nM. Pharmacokinetic studies of selected compounds showed that the in vivo clearance of S-22 was the slowest followed sequentially by S-20, S-21, and S-19. The dose-response relationships for S-22 showed that S-22 exerted efficacious and selective activity in anabolic tissues at dose rates as low as 0.03 mg/day, indicative of the high potency of this compound in anabolic tissue (relative potency 4.41) and its potential for clinical use in androgen deficiency-related disorders.

AB - Selective androgen receptor modulators (SARMs) have many potential therapeutic applications, including male hypogonadism, osteoporosis, muscle-wasting diseases, sexual libido, and contraception. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl) -propionamides bearing a four-halogen substituent in the B-ring that displayed in vivo activity were identified in our previous study. Interestingly, in vivo pharmacological activity was not correlated with in vitro androgen receptor (AR) binding affinity. In this study, analysis of the area under the concentration-time curve-response relationship demonstrated that the discrepancy between in vitro and in vivo pharmacological activity of these halogen-substituted SARMs was due to differences in systemic exposure rather than intrinsic pharmacological activity. Studies also suggested that two simple criteria (i.e., Ki < 10 nM and lower in vivo clearance) could be used to identify efficacious and potent SARMs. We tested this hypothesis using a series of four compounds incorporating either a nitro or cyano substituent at the para-position of the A- and B-aromatic rings. The S-3-(4-Nitrophenoxy) and S-3-(4-cyanophenoxy) 2-hydroxy-2-methyl-N-(4-nitro-3-trifluromethylphenyl) propionamides (S-19 and S-20, respectively) and S-3-(4-nitrophenoxy) and S-3-(4-cyanophenoxy) 2-hydroxy-2-methyl-N-(4-cyano-3-trifluromethylphenyl) propionamides (S-21 and S-22, respectively) demonstrated high AR binding affinity, with Ki values ranging from 2.0 to 3.8 nM. Pharmacokinetic studies of selected compounds showed that the in vivo clearance of S-22 was the slowest followed sequentially by S-20, S-21, and S-19. The dose-response relationships for S-22 showed that S-22 exerted efficacious and selective activity in anabolic tissues at dose rates as low as 0.03 mg/day, indicative of the high potency of this compound in anabolic tissue (relative potency 4.41) and its potential for clinical use in androgen deficiency-related disorders.

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