I guess this doesn't count as a "main" airport, but many airports served by Ryanair clearly fly into entirely different neighbourhoods.

Oslo Torp is a classic (2 hours away by coach) and Frankfurt Hahn (120km) come to mind.

Narita is probably the furthest (and most expensive) proper "first" airports I've come across. As a Londoner it's perhaps nice to be reminded that I don't live in quite the most overpriced and under-served capture area for a mainland airport (i.e. Heathrow).