CREB: nootropics and compounds | sci-wiki

Apremilast

Apremilast (Otezla) is an orally active PDE4 inhibitor and the first PDE4 drug ever FDA-approved for an immune-dermatologic indication (2014). By raising intracellular cAMP it recalibrates the immune system from the inside out, dialing down TNF-alpha, IL-23 and IL-17 while lifting anti-inflammatory IL-10. That single, elegant switch clears plaque psoriasis, calms psoriatic arthritis, and heals Behcet's oral ulcers, all from a convenient oral tablet that needs no lab monitoring.

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Respiratory

Cilomilast

Cilomilast (Ariflo) is a second-generation oral selective PDE4 inhibitor developed by GlaxoSmithKline for COPD and asthma. It reached FDA review but was rejected in 2003-2004 because the respiratory benefit was small and gastrointestinal side effects were dose-limiting. It is not approved anywhere. There is essentially no human cognition data; a single 2025 mouse study reported that cilomilast reversed scopolamine-induced memory deficits through the cAMP/PKA-CREB-BDNF pathway.

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Nootropic

HT-0712

HT-0712 (betamilast) is a PDE4 inhibitor purpose-engineered to be a memory drug. Designed across Inflazyme, Helicon and Dart NeuroScience, it targets the CREB memory pathway with a wider therapeutic window than the notoriously emetic rolipram. In animals it selectively boosts long-term (not short-term) memory in normal and aged mice, and it reached Phase 2 testing in age-associated memory impairment, making it the most deliberately memory-focused candidate in the PDE4 class.

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Neuroprotection

Piclamilast

Piclamilast (RP-73401) is a highly potent, subnanomolar pan-PDE4 inhibitor used mainly as a pharmacological reference tool and high-affinity rolipram-binding-site ligand. It was explored for COPD and asthma but never developed. Its most cognition-relevant finding is a 2022 mouse study in which post-ischemia piclamilast was neuroprotective and preserved memory through CREB, an effect abolished by a CREB inhibitor. There is no human data.

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Nootropic

Roflumilast

Roflumilast is a selective PDE4 inhibitor approved as a once-daily oral anti-inflammatory for severe COPD (Daliresp, Daxas) and as a topical treatment for psoriasis and other skin conditions (Zoryve). By blocking PDE4 it raises intracellular cAMP, calming inflammatory cells and, in the brain, boosting the CREB-to-BDNF signaling tied to learning and memory. That neuro angle has turned low, sub-emetic microdoses of roughly 100-250 micrograms into a genuinely intriguing but still preliminary nootropic candidate.

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Nootropic

Rolipram

Rolipram (ZK 62711) is the prototypical PDE4 inhibitor and the reference compound for the entire class. Developed by Schering as an antidepressant in the 1980s, it was abandoned over severe emesis but went on to become the single most-studied molecule in the cAMP/CREB-enhances-memory literature. It reliably converts early- to late-long-term potentiation and rescues memory across Alzheimer, aging and Rubinstein-Taybi models, making it the yardstick every newer PDE4 memory drug is measured against.

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