Tag: Cyclohexyl-carbonyl pyrrolidinone racetam

Fasoracetam (NS-105, NFC-1, LAM-105) is a synthetic nootropic of the racetam family, defined structurally as (5R)-5-(piperidine-1-carbonyl)pyrrolidin-2-one and distinguished from the canonical racetam piracetam by the substitution of a piperidine amide at the 5-position of the 2-pyrrolidinone ring. The compound was synthesized at Nippon Shinyaku Co., Ltd. in the mid-1980s and advanced through Phase 3 clinical trials in Japan for vascular dementia, an indication in which it failed to demonstrate statistically significant efficacy on cognitive endpoints and was subsequently abandoned by the originator. The pharmacological profile comprises three principal mechanisms: upregulation of gamma-aminobutyric acid type B (GABA-B) receptors in the cerebral cortex following repeated administration; activation of metabotropic glutamate receptors (mGluRs) across all three receptor groups (Group I, Group II, and Group III); and facilitation of cholinergic neurotransmission through enhanced high-affinity choline uptake and increased acetylcholine release from cortical and hippocampal neurons. These mechanisms were characterized in a series of rat studies conducted at Nippon Shinyaku during the 1990s, with the GABA-B upregulation and learned helplessness reversal reported by Oguchi et al. (1998), the cholinergic facilitation and anti-amnestic activity reported by Maeda et al. (1997), and the involvement of both cholinergic and GABAergic systems in memory disruption reversal confirmed by Ito et al. (1999). Preclinical pharmacology demonstrates reversal of scopolamine-induced amnesia in passive avoidance and radial arm maze paradigms, reversal of baclofen-induced amnesia, reduction of immobility time in the forced swimming test, and rescue of escape failure in the learned helplessness paradigm, with minimum effective doses as low as 0.1 mg/kg intraperitoneally for the active (5R) enantiomer. The compound was repurposed for attention deficit hyperactivity disorder (ADHD) following its acquisition by NeuroFix, Inc., which obtained the Nippon Shinyaku clinical data package and advanced the compound under the designation NFC-1. A five-week open-label, single-blind, placebo-controlled Phase 1/2 study in 30 adolescents with ADHD harboring mutations in mGluR network genes (Elia et al. 2018, Nature Communications) reported significant improvement on Clinical Global Impressions scales and parental Vanderbilt Assessment scores, with dose-proportional pharmacokinetics across the 50 to 800 mg dose range, a plasma elimination half-life of approximately 4 to 7 hours, rapid oral absorption with peak plasma concentrations at 1.3 to 1.9 hours, and oral bioavailability of 79 to 97 percent. The compound undergoes minimal hepatic metabolism and is excreted predominantly unchanged through the kidneys. There were no differences in adverse event incidence between placebo and active treatment weeks. Despite the ADHD pharmacogenomic signal, subsequent development has not produced a registration-enabling efficacy demonstration. NeuroFix was acquired by Medgenics (later Aevi Genomic Medicine, later Avalo Therapeutics), and development of fasoracetam for ADHD was deprioritized following disappointing efficacy results at scale. As of the most recent monograph revision, fasoracetam is under Phase 2 investigation by Nobias Therapeutics for 22q11.2 deletion syndrome (DiGeorge syndrome). The compound is not approved by any regulatory authority worldwide and is not marketed as a medicine. It is available as a research-grade preparation from multiple chemical suppliers. Investigators should obtain analytical confirmation of identity, purity, and enantiomeric configuration on every lot, as the (5R) enantiomer is the active isomer and the racemic mixture has reduced potency.