4-Alkyl- and 3,4-dialkyl-1,2,3,4,-tetrahydro-8-pyridono[5,6-g]quinolines: Potent, nonsteroidal androgen receptor agonists

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Abstract

A series of human androgen receptor (hAR) agonists based on 4-alkyl-; 4,4-dialkyl-; and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinoline was synthesized and evaluated in competitive receptor binding assays and an androgen receptor cotransfection assay in a mammalian cell background. A number of compounds in this series demonstrated activity equal to or better than dihydrotestosterone in both assays and represent a novel class of compounds for use in androgen replacement therapy.

Nonsteroidal androgen receptor (AR) agonists based on 4- and 3,4-substituted-1,2,3,4-tetrahydro-8-pyridono-[5,6-g]quinolines were synthesized and evaluated in hAR cotransfection and receptor binding assays. Several potent (2–10 nM) and efficacious (80–110%) AR agonists were discovered.

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1

Present Address: The R. W. Johnson Pharmaceutical Research Institute, 3535 General Atomics Court, San Diego, CA 92121.

2

Present Address: University of California-Berkeley, Department of Chemistry, Berkeley, CA.

3

Present Address: Ontogen Corporation, 2325 Camino Vida Roble, Carlsbad, CA 92009.

4

Present Address: Vertex Pharmaceuticals, Medicinal Chemistry, Cambridge, MA 02139.

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