Chemical Name: spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one
Therapy Type: Small Molecule (timeline)
Target Type: Unknown
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Company: Sonexa Therapeutics, Inc.
ST101 is an orally active azaindolizinone derivative that has been reported to be a cognitive enhancer. The compound may have pleiotropic effects. It has been reported to induce APP, cleave APP at a novel site that precludes subsequent Aβ generation, and reduce brain Aβ levels and improve memory function in transgenic mice and non-human primates (Green et al., 2011). ST101 also has been reported to stimulate the cholingergic system, activate a number of intracellular signaling pathways such as ERK1/2 following stimulation with dopamine D1 and NMDA receptors, and target voltage-gated calcium channels (Shioda et al., 2011; Ito et al., 2007; Moriguchi et al., 2012). One preclinical study in the senescence-accelerated prone mouse strain 8 (SAMP8) reported a treatment effect on behavioral assays and brain amyloid deposition (Yamaguchi et al., 2012).
Two Phase 2 trials in Alzheimer's disease, conducted at multiple sites in the United States and Canada, have been completed. One compared three doses of ST101 to placebo in 168 people with mild to moderate Alzheimer's disease on the ADAS-cog, ADCS-ADL, and ADCS-GCI. This trial ended in September 2010. The other trial compared three lower doses of ST101 to placebo in 210 people with mild to moderate AD who also were on donepezil treatment against the same outcome measures. Results have not been reported in the literature.
In 2011, Sonexa also ran a small proof-of-concept study comparing ST101 tablets to placebo in 25 people with essential tremor. For all trials of ST101 see clinicaltrials.gov.
- Green KN, Khashwji H, Estrada T, Laferla FM. ST101 induces a novel 17 kDa APP cleavage that precludes Aβ generation in vivo. Ann Neurol. 2011 May;69(5):831-44. PubMed.
- Shioda N, Yamamoto Y, Han F, Moriguchi S, Fukunaga K. [Neurochemical mechanisms of a novel Alzheimer's disease therapeutics on improvement of cognition and depressive behavior]. Yakugaku Zasshi. 2011 Apr;131(4):505-11. PubMed.
- Ito Y, Takuma K, Mizoguchi H, Nagai T, Yamada K. A novel azaindolizinone derivative ZSET1446 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) improves methamphetamine-induced impairment of recognition memory in mice by activating extracellular signal-regulated kinase 1/2. J Pharmacol Exp Ther. 2007 Feb;320(2):819-27. Epub 2006 Nov 7 PubMed.
- Moriguchi S, Shioda N, Yamamoto Y, Tagashira H, Fukunaga K. The T-type voltage-gated calcium channel as a molecular target of the novel cognitive enhancer ST101: enhancement of long-term potentiation and CaMKII autophosphorylation in rat cortical slices. J Neurochem. 2012 Apr;121(1):44-53. PubMed.
- Yamaguchi Y, Saito K, Matsuno T, Takeda K, Hino M. Effects of ZSET1446/ST101 on cognitive deficits and amyloid β deposition in the senescence accelerated prone mouse brain. J Pharmacol Sci. 2012;119(2):160-6. PubMed.
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