Allergan Sales, Inc.

Allergan, Inc.

Andrew M Standeven

Roshantha A Chandraratna

Richard L Beard

Min Teng

Vidyasagar Pradeep Vuligonda

Alan T Johnson

Tien T Duong

Sunil Nagpal

Samuel J Gillett

Elliott S Klein

Elliot S Klein

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.

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Corona Del Mar, CA, United States of America

Andrew M Standeven