The pair will play 1960s human-sexuality science pioneers William Masters and Virginia Johnson.
The pilot is to be directed by Academy Award nominee John Madden in New York next month.
Sheen's film credits include "Midnight in Paris," "The Queen," "Frost/Nixon," and the "Twilight" and "Underworld" franchises.
Caplan has appeared in the movies "Mean Girls," "Hot Tub Time Machine," "Cloverfield," "My Best Friend's Girl," "Crossing Over" and "The Last Rites of Ransom Pride." She also plays a recurring role on TV's "New Girl."
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