Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators

Lawrence G. Hamann, Mark C. Manfredi, Chongqing Sun, Stanley R. Krystek, Yanting Huang, Yingzhi Bi, David Augeri, Tammy Wang, Yan Zou, David A. Betebenner, Aberra Fura, Ramakrishna Seethala, Rajasree Golla, Joyce E. Kuhns, John A. Lupisella, Celia J. Darienzo, Laura L. Custer, Jennifer L. Price, James M. Johnson, Scott A. Biller & 2 others Robert Zahler, Jacek Ostrowski

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Pharmacokinetic studies in cynomolgus monkeys with a novel prototype selective androgen receptor modulator revealed trace amounts of an aniline fragment released through hydrolytic metabolism. This aniline fragment was determined to be mutagenic in an Ames assay. Subsequent concurrent optimization for target activity and avoidance of mutagenicity led to the identification of a pharmacologically superior clinical candidate without mutagenic potential.

Original languageEnglish (US)
Pages (from-to)1860-1864
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume17
Issue number7
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

Fingerprint

Hydantoins
Androgen Receptors
Modulators
Pharmacokinetics
Macaca fascicularis
Metabolism
Assays
aniline

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Clinical Biochemistry
  • Pharmaceutical Science
  • Organic Chemistry

Cite this

Hamann, Lawrence G. ; Manfredi, Mark C. ; Sun, Chongqing ; Krystek, Stanley R. ; Huang, Yanting ; Bi, Yingzhi ; Augeri, David ; Wang, Tammy ; Zou, Yan ; Betebenner, David A. ; Fura, Aberra ; Seethala, Ramakrishna ; Golla, Rajasree ; Kuhns, Joyce E. ; Lupisella, John A. ; Darienzo, Celia J. ; Custer, Laura L. ; Price, Jennifer L. ; Johnson, James M. ; Biller, Scott A. ; Zahler, Robert ; Ostrowski, Jacek. / Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators. In: Bioorganic and Medicinal Chemistry Letters. 2007 ; Vol. 17, No. 7. pp. 1860-1864.
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abstract = "Pharmacokinetic studies in cynomolgus monkeys with a novel prototype selective androgen receptor modulator revealed trace amounts of an aniline fragment released through hydrolytic metabolism. This aniline fragment was determined to be mutagenic in an Ames assay. Subsequent concurrent optimization for target activity and avoidance of mutagenicity led to the identification of a pharmacologically superior clinical candidate without mutagenic potential.",
author = "Hamann, {Lawrence G.} and Manfredi, {Mark C.} and Chongqing Sun and Krystek, {Stanley R.} and Yanting Huang and Yingzhi Bi and David Augeri and Tammy Wang and Yan Zou and Betebenner, {David A.} and Aberra Fura and Ramakrishna Seethala and Rajasree Golla and Kuhns, {Joyce E.} and Lupisella, {John A.} and Darienzo, {Celia J.} and Custer, {Laura L.} and Price, {Jennifer L.} and Johnson, {James M.} and Biller, {Scott A.} and Robert Zahler and Jacek Ostrowski",
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Hamann, LG, Manfredi, MC, Sun, C, Krystek, SR, Huang, Y, Bi, Y, Augeri, D, Wang, T, Zou, Y, Betebenner, DA, Fura, A, Seethala, R, Golla, R, Kuhns, JE, Lupisella, JA, Darienzo, CJ, Custer, LL, Price, JL, Johnson, JM, Biller, SA, Zahler, R & Ostrowski, J 2007, 'Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators', Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 7, pp. 1860-1864. https://doi.org/10.1016/j.bmcl.2007.01.076

Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators. / Hamann, Lawrence G.; Manfredi, Mark C.; Sun, Chongqing; Krystek, Stanley R.; Huang, Yanting; Bi, Yingzhi; Augeri, David; Wang, Tammy; Zou, Yan; Betebenner, David A.; Fura, Aberra; Seethala, Ramakrishna; Golla, Rajasree; Kuhns, Joyce E.; Lupisella, John A.; Darienzo, Celia J.; Custer, Laura L.; Price, Jennifer L.; Johnson, James M.; Biller, Scott A.; Zahler, Robert; Ostrowski, Jacek.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 17, No. 7, 01.04.2007, p. 1860-1864.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators

AU - Hamann, Lawrence G.

AU - Manfredi, Mark C.

AU - Sun, Chongqing

AU - Krystek, Stanley R.

AU - Huang, Yanting

AU - Bi, Yingzhi

AU - Augeri, David

AU - Wang, Tammy

AU - Zou, Yan

AU - Betebenner, David A.

AU - Fura, Aberra

AU - Seethala, Ramakrishna

AU - Golla, Rajasree

AU - Kuhns, Joyce E.

AU - Lupisella, John A.

AU - Darienzo, Celia J.

AU - Custer, Laura L.

AU - Price, Jennifer L.

AU - Johnson, James M.

AU - Biller, Scott A.

AU - Zahler, Robert

AU - Ostrowski, Jacek

PY - 2007/4/1

Y1 - 2007/4/1

N2 - Pharmacokinetic studies in cynomolgus monkeys with a novel prototype selective androgen receptor modulator revealed trace amounts of an aniline fragment released through hydrolytic metabolism. This aniline fragment was determined to be mutagenic in an Ames assay. Subsequent concurrent optimization for target activity and avoidance of mutagenicity led to the identification of a pharmacologically superior clinical candidate without mutagenic potential.

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

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