Pyrazolo-Pyrimidinones\nwith Improved Solubility and\nSelective Inhibition of Adenylyl Cyclase Type 1 Activity for Treatment\nof Inflammatory Pain

Adenylyl cyclase isoform 1 (AC1) is considered a promising\ntarget\nfor treating inflammatory pain. Our group identified the pyrazolyl-pyrimidinone\nscaffold as potent and selective inhibitors of Ca<sup>2+</sup>/CaM-mediated\nAC1 activity; however, the molecules suffered from poor aqueous solubility.\nThe current study presents a strategy to improve aqueous solubility\nof the scaffold by reduction of crystal packing energy and increasing\nrotational degrees of freedom within the molecule. Structure–activity\nand property relationship studies identified the second generation\nlead <b>7-47A</b> (<b>AC10142A</b>) that demonstrated\nand AC1 IC<sub>50</sub> value of 0.26 μM and aqueous solubility\nof 74 ± 7 μM. After in vitro ADME characterization, the\nscaffold advanced to in vivo pharmacokinetic evaluation, demonstrating\nadequate levels of exposure. Finally, <b>7-47A</b> exhibited\nantiallodynic efficacy in a rat complete Freund’s adjuvant\nmodel for inflammatory pain showing improvement over previous iterations\nof this scaffold. These results further validate AC1 inhibition as\na viable therapeutic strategy for treating chronic and inflammatory\npain.