BPN14770 (Zatolmilast) 5mg – 60 tablets

BPN14770 / Zatolmilast 5 mg — 60 oral research tablets. Zatolmilast (BPN14770) is the most clinically advanced selective allosteric inhibitor of phosphodiesterase 4D (PDE4D) ever developed — and arguably the most important new chemotype to emerge from intellectual-disability research in the past decade. Originally developed at Tetra Therapeutics (now part of Shionogi), BPN14770 has progressed through Phase II clinical trials in Fragile X syndrome with statistically significant improvements in cognitive composite scores, language and daily-living function, and is currently in Phase III development. Unlike older non-selective PDE4 inhibitors (rolipram, roflumilast), BPN14770’s allosteric mechanism preserves cAMP signaling under physiological conditions and produces dose-dependent cognitive enhancement without the emetic and tolerability ceiling that has limited the entire PDE4 class for decades.

Research Overview

Phosphodiesterase 4D (PDE4D) is the predominant cAMP-degrading enzyme in mammalian brain, and pharmacological inhibition of PDE4 has long been recognized as a potent strategy for enhancing memory and synaptic plasticity — first demonstrated decades ago with the prototype molecule rolipram [1]. The clinical promise of PDE4 inhibition has, however, been blocked for forty years by the emetic and GI side-effect profile shared by every non-selective PDE4 inhibitor, including the approved COPD drug roflumilast. BPN14770 is the first fundamentally new approach to this problem: it is a selective allosteric inhibitor of PDE4D that binds outside the catalytic site, producing partial — rather than complete — inhibition that preserves baseline cAMP signaling and abolishes the dose-limiting emesis [1,2]. In a Phase II RCT in adult males with Fragile X syndrome (Berry-Kravis et al., Nat Med 2021), 12-week BPN14770 produced statistically significant improvements in cognitive composite, language, and daily-living function — the first ever positive cognitive-endpoint result in any Fragile X clinical trial [2]. The compound has now advanced into Phase III development and is widely considered the most promising new pharmacological strategy for intellectual disability and age-related cognitive decline [3].

Primary Research Areas

• PDE4D allosteric inhibitor pharmacology — the lead clinical-stage allosteric PDE4D inhibitor; the cleanest available chemical probe of partial-inhibition pharmacology in the cAMP pathway [1,2].
• Fragile X syndrome research — the first molecule to produce a positive cognitive-endpoint signal in any Fragile X clinical trial — Phase II/III development in Fragile X is ongoing [2].
• Memory and synaptic plasticity — robust enhancement of LTP, working memory and long-term memory consolidation in rodent models [1].
• Neurodevelopmental and intellectual-disability research — investigated as a clinical-stage approach to genetic intellectual disabilities beyond Fragile X [3].
• Age-related cognitive decline — the partial-inhibition pharmacology and tolerability profile open the PDE4 class to chronic cognitive-aging research for the first time [1,3].

References

1. Gurney ME, Cogram P, Deacon RM, Rex C, Tranfaglia M. Multiple behavior phenotypes of the fragile-X syndrome mouse model respond to chronic inhibition of phosphodiesterase-4D (PDE4D). Sci Rep. 2017;7(1):14653.
2. Berry-Kravis EM, Harnett MD, Reines SA, et al. Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, Phase 2 clinical trial. Nat Med. 2021;27(5):862–870.
3. Pelan SE, Anderson J, Beach J, et al. Selective inhibition of PDE4D for the treatment of fragile X syndrome and other intellectual disabilities. Pharmacol Ther. 2023;241:108310.