Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice

Abstract

Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issue, conservation of the catalytic region, to which classical inhibitors bind, limits this approach. The present study examined the effects of BPN14770, an allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region. In mice engineered to express PDE4D with this primate-specific sequence, BPN14770 was 100-fold more potent for improving memory than in wild-type mice; meanwhile, it exhibited low potency in a mouse surrogate model for emesis. BPN14770 also antagonized the amnesic effects of scopolamine, increased cAMP signaling in brain, and increased BDNF and markers of neuronal plasticity associated with memory. These data establish a relationship between PDE4D target engagement and effects on memory for BPN14770 and suggest clinical potential for PDE4D-selective inhibitors.

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

“…In a press release, BPN14770 was described as having good safety and oral bioavailability and an ability to improve working memory in healthy elderly adults (http://tetradiscovery.com/wp-content/uploads/2016/11/FINAL-Tetra-Phase-1-121616-FINAL.pdf; accessed 04/30/19). These effects in humans are consistent with preclinical studies showing BPN14770 improved a number of behaviors in a mouse model of Fragile-X Syndrome and antagonized the amnestic effects of scopolamine in mice (134,135). Based on preclinical studies showing anxiolytic and cognitionenhancing effects (136), the PDE4i GSK356278 entered Phase I safety trials for Huntington's disease but adverse events limited the highest dose to that achieving only ~50% occupancy in brain (Table 3; 136 McCune-Albright Syndrome is a disease affecting endocrine tissues, skin and bones and is caused by a mutation that results in constitutive activation of the G-protein alpha subunit Gαs (Gαs*).…”

“…Although the challenge of targeting localized pools of PDEs for purposes of correcting pockets of aberrant cyclic nucleotide signaling has proven difficult in the past, there are indications that innovative approaches and technological advances are making headway (see Table 4 for recent patent activity that includes PDE activators, biomarkers, and viral approaches). For example, agents that show remarkable selectivity for subfamilies of PDE4 are showing promising results in mouse models of learning and memory and translation to human disease would be a game changing advance (135). Additionally, novel delivery systems are being developed that can transport PDE inhibitors to precise tissues or cell types, thereby abrogating complications associated with systemic distribution (e.g., (293,294)).…”

“…Indeed, PKA, PKG, and Epacs have been implicated as therapeutic targets in their own right for a number of indications for which PDEi's are being pursued, including diseases of the cardiovascular, immune, and nervous systems as well as cancer (e.g., (129,130,(296)(297)(298)(299)(300)). Further, several studies in a variety of tissues have attributed the beneficial effects of PDEi's to the activation of PKA, PKG and/or Epac (e.g., (135,(301)(302)(303)). As we learn more about the functional role and molecular interactions of each PDE splice variant, and how the function and/or localization of an individual variant may be altered in a given disease, it will become clearer how we can successfully target PDEs in a specific fashion to achieve efficacy while avoiding side effects.…”

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

“…It seems that this compound is safe and well tolerated, according to a multiple ascending dose investigation . In a recent study by Zhang et al., it was considered that BPN14770 inhibits PDE4D allosterically by binding to a primate‐specific N‐terminal region of the enzyme. They used humanized mice in which the mouse PDE4D gene was genetically engineered to test this compound, and the results strongly support that allosteric inhibitors of PDE4D are able to modulate neurochemical and cognitive biomarkers of protein kinase A (PKA)‐CREB pathway outflow.…”

Dominant-Negative Attenuation of cAMP-Selective Phosphodiesterase PDE4D Action Affects Learning and Behavior

“…Highly selective inhibitors of the PDE4, 3′, 5′-cAMP-specific phosphodiesterases have proven cognition-enhancing and antidepressant properties in humans [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ] and rodents [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. PDE4-selective inhibitors are exploited therapeutically for their anti-inflammatory, immunomodulatory and smooth-muscle relaxant activities (for reviews, see [ 49 , 50 , 51 ]).…”