The second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) regulate a myriad of processes. They include cell proliferation, differentiation, apoptosis, inflammation, hormone secre-tion, muscle contraction, and cognitive functions. Intracellular cAMP and cGMP levels are determined by the balance between their synthesis by adenylate or guanylate cyclases. In addition, Their degradation is by phosphodiesterases (PDEs). In mammals, 21 genes encode 100 PDE isoforms. PDE11 is one of the PDE family members. In humans the PDE11A gene encodes four isoforms that are dual-specificity enzymes, hydrolyzing both cAMP and cGMP. PDE11A knockout mice display subtle alterations in sperm function and psychiatric disease-related phenotypes. The absence of more dramatic phenotypes may be due to compensation by other PDEs during development that masks normalroles for PDE11. In this study, BC11-38 is a potent, selective, and biologically active PDE11 inhibitor.
The skeletal muscle, prostate, testis, brain, kidney, liver, pancreas, lymphoid cells, and pituitary and adrenal glands express PDE11A. Genetic defects of PDE11A related to major depression, bipolar disorder, asthma, adrenal, testicular, and prostatic cancers in genome-wide association studies. In addition, inactivating mutations of PDE11A in patients show relations in several forms of adrenal hyperplasia and Cushing syndrome, which results from excess cortisol release from adrenocortical tumors. BC11-38 is a potent, selective PDE11 inhibitor, with IC50s of 0.28 µM and >100 µM for PDE11 and PDE1-10, respectively. Moreover, BC11-38 elevates cAMP levels, PKA-mediated ATF-1 phosphorylation, and cortisol production in H295R cells.
In summary, BC11-38 is a potent, selective, and biologically active PDE11 inhibitor. In addition, BC11-38, along with two derivatives, elevates cAMP levels and cortisol production in adrenocortical cells in a PDE11-specific manner, mimicking the phenotypes observed in Cushing syndrome.