Pyrazolo-Pyrimidinones with Improved Solubility and Selective Inhibition of Adenylyl Cyclase Type 1 Activity for Treatment of Inflammatory Pain

Adenylyl cyclase isoform 1 (AC1) is considered a promising
target
for treating inflammatory pain. Our group identified the pyrazolyl-pyrimidinone
scaffold as potent and selective inhibitors of Ca2+/CaM-mediated
AC1 activity; however, the molecules suffered from poor aqueous solubility.
The current study presents a strategy to improve aqueous solubility
of the scaffold by reduction of crystal packing energy and increasing
rotational degrees of freedom within the molecule. Structure–activity
and property relationship studies identified the second generation
lead 7-47A (AC10142A) that demonstrated
and AC1 IC50 value of 0.26 μM and aqueous solubility
of 74 ± 7 μM. After in vitro ADME characterization, the
scaffold advanced to in vivo pharmacokinetic evaluation, demonstrating
adequate levels of exposure. Finally, 7-47A exhibited
antiallodynic efficacy in a rat complete Freund’s adjuvant
model for inflammatory pain showing improvement over previous iterations
of this scaffold. These results further validate AC1 inhibition as
a viable therapeutic strategy for treating chronic and inflammatory
pain.