Abstract
Herein we describe the discovery of ACP-105 (1), a novel and potent nonsteroidal selective androgen receptor modulator (SARM) with partial agonist activity relative to the natural androgen testosterone. Compound 1 was developed from a series of compounds found in a HTS screen using the receptor selection and amplification technology (R-SAT). In vivo, 1 improved anabolic parameters in a 2-week chronic study in castrated male rats. In addition to compound 1, a number of potent antiandrogens were discovered from the same series of compounds whereof one compound, 13, had antagonist activity at the AR T877A mutant involved in prostate cancer.
MeSH terms
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Administration, Oral
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Androgen Receptor Antagonists*
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Androgens*
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Animals
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Azabicyclo Compounds / chemistry*
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Azabicyclo Compounds / metabolism
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Azabicyclo Compounds / pharmacokinetics
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Azabicyclo Compounds / pharmacology*
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Dogs
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Drug Design
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Humans
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Ligands
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Male
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Mice
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Microsomes, Liver / metabolism
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Mutation
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NIH 3T3 Cells
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Orchiectomy
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Prostatic Neoplasms / genetics
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Rats
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism
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Structure-Activity Relationship
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Substrate Specificity
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Testosterone Propionate / pharmacology
Substances
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2-chloro-4-(3-hydroxy-3-methyl-8-azabicyclo(3.2.1)oct-8-yl)-3-methylbenzonitrile
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Androgen Receptor Antagonists
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Androgens
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Azabicyclo Compounds
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Ligands
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Receptors, Androgen
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Testosterone Propionate