Cyclic Surrogates Pass The Acid Test

Chemists seeking molecular substitutes, or isosteres, for carboxylic acids can add another functional group to their tool kits: cyclopentane-1,3-diones. Carboxylic acids often mediate drug candidate interactions with biological targets, but these functional groups carry baggage, including metabolic instability. While searching for suitable surrogates, Amos B. Smith III of the University of Pennsylvania recalled his mentor, Rockefeller University’s William C. Agosta, informing him about the dione moiety’s acidity many years before. So Smith, Carlo Ballatore, and colleagues decided to try it out. The tactic using cyclopentane-1,3-diones worked well for the team in devising potent blockers of the thromboxane receptor, a key player in blood clotting (J. Med. Chem., DOI: 10.1021/jm200980u). When it comes to isosteres in drug discovery, more options are always better, says medicinal chemist R. Jason Herr of Albany Molecular Research Inc. Because dione lipophilicity is tunable and the moiety can be attached at two points, it offers myriad options, Herr adds. “In hindsight, it truly is amazing that no one has thought to try using this functional group as a carboxylic acid surrogate before now,” he says.