Therapeutics

ABT-957

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Overview

Name: ABT-957
Synonyms: Alicapistat
Chemical Name: (2R)-1-benzyl-N-[4-(cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl]-5-oxopyrrolidine-2-carboxamide
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: AbbVie

Background

This compound is an inhibitor of the calcium-dependent cysteine protease calpain. This enzyme has long been known to be highly active in Alzheimer’s disease brain (Saito et al., 1993), but its different isoforms, numerous substrates, and pleiotropic effects made drug discovery difficult. Calpain became an active therapeutic target as more specific inhibitors have become available. The structure, synthesis, and selectivity of ABT-957 has been published (Jantos et al., 2019).

Calpain is thought to play a role in several of the pathophysiological processes underlying neurodegeneration. For example, calpain functions in NMDR signaling cascades that lead to neuronal excitotoxicity. It has also been reported to mediate Aβ-induced synaptic dysfunction by cleaving the synaptic vesicle protein dynamin 1 (e.g., Wu et al., 2004; Kelly et al., 2005). Calpain cleaves p35 to release p25, an activating protein for the tau kinase cyclin-dependent kinase 5, and excess calpain activation has been linked to hyperphosphorylation of tau and its subsequent aggregation into neurofibrillary tangles. In a tauopathy mouse model, genetic calpain reduction prevented neurodegeneration (see Noble et al., 2003; Rao et al., 2014). 

Preclinical studies with small-molecule calpain inhibitors have shown improvement of behavioral deficits in models of excitotoxicity of the nucleus basalis of Meynert, a brain area involved in AD. This effect was attributed to the inhibitor’s ability to stanch cholinergic neurodegeneration. In hippocampal slice culture, calpain inhibition reportedly prevented both excitotoxic neuronal death and deficits in neurotransmission brought on by Aβ oligomers. In rats, calpain inhibition dose-dependently protected neurons against degeneration caused by Aβ oligomers, and it prevented gliosis (Nimmrich et al., 2008; Nimmrich et al., 2010; Granic et al., 2010). 

Findings

In August 2014, AbbVie started enrolling 20 people with mild to moderate Alzheimer’s disease into a Phase 1 trial of ABT-957. This multicenter study planned to expose participants to the study drug or placebo twice daily for a week and measure pharmacokinetic and safety parameters. It was originally slated to end in March 2015, but after a temporary suspension was expected to run through February 2016. The study ended in March 2016 with 19 participants. 

In December 2015, a second Phase 1 study began enrolling 50 people with MCI due to AD or probable AD. This study was to be conducted in six U.S. states; and compare safety and tolerability of multiple doses of ABT-957 given twice daily for 12 weeks. In addition, this study was to measure CSF levels of spectrin breakdown product-145. SBDP-145 is considered a biomarker of calpain activity (Warren et al., 2007). This trial was terminated in June 2016 after enrolling only eight participants, citing insufficient target engagement based on preclinical data.

The results of these and additional trials in the Phase 1 program were subsequently published (Lon et al., 2018). Drug concentrations in the CNS did not reach levels sufficient to produce a pharmacodynamic effect, as assessed by changes in REM sleep behavior. The program was terminated.

For clinical trials of this compound, see clinicaltrials.gov.  

Last Updated: 04 Nov 2022

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References

Paper Citations

  1. Warren MW, Larner SF, Kobeissy FH, Brezing CA, Jeung JA, Hayes RL, Gold MS, Wang KK. Calpain and caspase proteolytic markers co-localize with rat cortical neurons after exposure to methamphetamine and MDMA. Acta Neuropathol. 2007 Sep;114(3):277-86. Epub 2007 Jul 24 PubMed.
  2. Lon HK, Mendonca N, Goss S, Othman AA, Locke C, Jin Z, Rendenbach-Mueller B. Pharmacokinetics, Safety, Tolerability, and Pharmacodynamics of Alicapistat, a Selective Inhibitor of Human Calpains 1 and 2 for the Treatment of Alzheimer Disease: An Overview of Phase 1 Studies. Clin Pharmacol Drug Dev. 2018 Jul 27; PubMed.
  3. Saito K, Elce JS, Hamos JE, Nixon RA. Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2628-32. PubMed.
  4. Jantos K, Kling A, Mack H, Hornberger W, Moeller A, Nimmrich V, Lao Y, Nijsen M. Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with enhanced metabolic stability. Bioorg Med Chem Lett. 2019 Aug 1;29(15):1968-1973. Epub 2019 May 18 PubMed.
  5. Wu HY, Tomizawa K, Oda Y, Wei FY, Lu YF, Matsushita M, Li ST, Moriwaki A, Matsui H. Critical role of calpain-mediated cleavage of calcineurin in excitotoxic neurodegeneration. J Biol Chem. 2004 Feb 6;279(6):4929-40. Epub 2003 Nov 19 PubMed.
  6. Kelly BL, Vassar R, Ferreira A. Beta-amyloid-induced dynamin 1 depletion in hippocampal neurons. A potential mechanism for early cognitive decline in Alzheimer disease. J Biol Chem. 2005 Sep 9;280(36):31746-53. PubMed.
  7. Noble W, Olm V, Takata K, Casey E, Mary O, Meyerson J, Gaynor K, LaFrancois J, Wang L, Kondo T, Davies P, Burns M, Veeranna, Nixon R, Dickson D, Matsuoka Y, Ahlijanian M, Lau LF, Duff K. Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron. 2003 May 22;38(4):555-65. PubMed.
  8. Rao MV, McBrayer MK, Campbell J, Kumar A, Hashim A, Sershen H, Stavrides PH, Ohno M, Hutton M, Nixon RA. Specific calpain inhibition by calpastatin prevents tauopathy and neurodegeneration and restores normal lifespan in tau P301L mice. J Neurosci. 2014 Jul 9;34(28):9222-34. PubMed.
  9. Nimmrich V, Szabo R, Nyakas C, Granic I, Reymann KG, Schröder UH, Gross G, Schoemaker H, Wicke K, Möller A, Luiten P. Inhibition of Calpain Prevents N-Methyl-D-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral Dysfunction. J Pharmacol Exp Ther. 2008 Nov;327(2):343-52. Epub 2008 Aug 13 PubMed.
  10. Nimmrich V, Reymann KG, Strassburger M, Schöder UH, Gross G, Hahn A, Schoemaker H, Wicke K, Möller A. Inhibition of calpain prevents NMDA-induced cell death and beta-amyloid-induced synaptic dysfunction in hippocampal slice cultures. Br J Pharmacol. 2010 Apr;159(7):1523-31. Epub 2010 Mar 3 PubMed.
  11. Granic I, Nyakas C, Luiten PG, Eisel UL, Halmy LG, Gross G, Schoemaker H, Möller A, Nimmrich V. Calpain inhibition prevents amyloid-beta-induced neurodegeneration and associated behavioral dysfunction in rats. Neuropharmacology. 2010 Sep-Oct;59(4-5):334-42. Epub 2010 Jul 23 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Getz GS. Calpain inhibition as a potential treatment of Alzheimer's disease. Am J Pathol. 2012 Aug;181(2):388-91. PubMed.
  2. Medeiros R, Kitazawa M, Chabrier MA, Cheng D, Baglietto-Vargas D, Kling A, Moeller A, Green KN, Laferla FM. Calpain Inhibitor A-705253 Mitigates Alzheimer's Disease-Like Pathology and Cognitive Decline in Aged 3xTgAD Mice. Am J Pathol. 2012 Aug;181(2):616-25. PubMed.
  3. Nikkel AL, Martino B, Markosyan S, Brederson JD, Medeiros R, Moeller A, Bitner RS. The novel calpain inhibitor A-705253 prevents stress-induced tau hyperphosphorylation in vitro and in vivo. Neuropharmacology. 2012 Sep;63(4):606-12. PubMed.
  4. Trinchese F, Fa' M, Liu S, Zhang H, Hidalgo A, Schmidt SD, Yamaguchi H, Yoshii N, Mathews PM, Nixon RA, Arancio O. Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease. J Clin Invest. 2008 Aug;118(8):2796-807. PubMed.
  5. Saito K, Elce JS, Hamos JE, Nixon RA. Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2628-32. PubMed.
  6. Jastaniah A, Gaisina IN, Knopp RC, Thatcher GR. Synthesis of α-Ketoamide-Based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents. ChemMedChem. 2020 Dec 3;15(23):2280-2285. Epub 2020 Sep 18 PubMed.
  7. Knopp RC, Jastaniah A, Dubrovskyi O, Gaisina I, Tai L, Thatcher GR. Extending the Calpain-Cathepsin Hypothesis to the Neurovasculature: Protection of Brain Endothelial Cells and Mice from Neurotrauma. ACS Pharmacol Transl Sci. 2021 Feb 12;4(1):372-385. Epub 2021 Feb 2 PubMed.