Ocular Hypotensive Activity of Prostaglandin F2α (PGF2α) Analogs with Neutral Substituents at Position 1 is Predicted by the Isolated Cat Iris Sphincter Smooth Muscle Preparation but not Ca+ Signalling in Swiss 3T3 Cells

Typically, the C-1 carboxylic acid (CO2H) has been considered an essential pharmacophoric group for ligand binding to the FP-receptor. Historically, in drug design and development, a formal negatively charged carboxylic acid can be replaced with a group of similar pKa, such as tetrazole or an acyl sulfonamide. This change sometimes provides better selectivity and/or increased potency due to better metabolic stability. We investigated replacement of the C-1 carboxylic acid with a variety of uncharged C-1 substituents. A diverse series of Cl-analogs was synthesized and certain compounds, especially AGN-191129 (PGF2aOCH3), exhibited an apparent unique pharmacology, thus confiming the importance of the Cl-CO2H for binding to the FP-receptor.