I was in the same boat about a month ago. I was upgrading from my 2005 S430 and at first was looking at the 2007 S550, but many had hire miles and was short on some of the new features I was interested in. I then had my mind on a 2009 or 2010, especially the 2010's since at that time all were face lifted, I saw some 2009's with the face lifted look and some 2009's without it. The price range for them around me were around $30-40K for a good one. I test drove the 2008,2008,2009,2010,2011 and 2012 S550's. In the end, i coughed up more then i anticipated and purchased the 2012 S550. If a possibility I would recommend a 2012 or 2013. Starting in MY 2012 they started to use the Twin Turbo 4.6 V8'S and compared the the previous model years, its pick up just felt more right for a big car like these W221's. As other members are saying, look for one with low miles and BUY AND EXTENDED WARRANTY! I purchased a exclusion warranty that would cover me to 101,000 Miles or until 2019, and sadly as already come in handy with about $500 repair. I don't know where you live, but in my area there are a ton of Mercedes W221's to choose from so they are out there. All in all I paid around $60,000 for my 2012 S550 with the drivers assistance package (Active blind spot, Active lane keeping assist and distronic plus), Rear seat entertainment system, Night vision, heated steering wheel, Premium 2 Package and Panoramic roof and the extended warranty. Only thing I wish I could have gotten but could not find is one with the Bang and Olufesn sound system.
If a 2012 or 2013 is not an option, I would recommend a 2010 or newer, but with less miles than 77K, trust me it is worth paying more for less miles and getting an extended warranty with which ever MY you get.
Good Luck! The W221 is fun and exciting to drive!