Allergan, Inc.

Allergan Sales, Inc.

Elliott S Klein

Roshantha A Chandraratna

Sunil Nagpal

Richard L Beard

Min Teng

Vidyasagar Pradeep Vuligonda

Alan T Johnson

Tien T Duong

Samuel J Gillett

Andrew M Standeven

Yang-Dar Yuan

Methods of characterizing and identifying negative hormones of nuclear receptors. Also disclosed are methods of making modulators of retinoid nuclear receptor transactivation activity, assays for agonists, antagonists, and negative hormones of the RAR receptor, and specific retinoid modulators of retinoid nuclear receptors.

Methods of identifying compounds having nuclear receptor negative hormone and/or antagonist activities

Methods and compositions for inhibiting or preventing spermatogenesis in a male mammal. Also disclosed are compounds and formulations for use in such methods.

Male anti-fertility agents

Aryl-substituted and aryl and (3-oxo-1-propenly)-substituted benzopyran, benzothiopyran, 1,2-dihydroquinoline, and 5,6-dihydronaphthalene derivatives have retinoid negative hormone and/or antagonist-like biological activities. The invented RAR antagonists can be administered to mammals, including humans, for the purpose of preventing or diminishing action of RAR agonists on the bound receptor sites. Specifically, the RAR agonists are administered or coadministered with retinoid drugs to prevent or ameliorate toxicity or side effects caused by retinoids or vitamin A or vitamin A precursors. The retinoid negative hormones can be used to potentiate the activities of other retinoids and nuclear receptor agonists. For example, the retinoid negative hormone called AGN 193109 effectively increased the effectiveness of other retinoids and steroid hormones in in vitro transactivation assays. Additionally, transactivation assays can be used to identify compounds having negative hormone activity. These assays are based on the ability of negative hormones to down-regulate the activity of chimeric retinoid receptors engineered to possess a constitutive transcription activator domain.

Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities

Synthesis and use of retinoid compounds having negative hormone and/or anatgonist activities

Synthesis and use of retinoid compounds having negative hormone and/or

2,2-Dialkyl-4-aryl-substituted benzopyran and benzothiopyran derivatives of the formula ##STR1## where the symbols have the meaning described in the specification, have retinoid negative hormone and/or antagonist-like biological activities. The invented RAR antagonists can be administered to mammals, including humans, for the purpose of preventing or diminishing action of RAR agonists on the bound receptor sites. Specifically, the RAR agonists are administered or coadministered with retinoid drugs to prevent or ameliorate toxicity or side effects caused by retinoids or vitamin A or vitamin A precursors. The retinoid negative hormones can be used to potentiate the activities of other retinoids and nuclear receptor agonists.

Method of identifying negative hormone and/or antagonist activities

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Marina Del Ray, CA, United States of America

Elliott S Klein