Display options
Cite
Peng H, Talreja T, Xin Z, et al. Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator. ACS Med Chem Lett. 2011;2(10):786-91doi: 10.1021/ml200175q.
Peng, H., Talreja, T., Xin, Z., Cuervo, J. H., Kumaravel, G., Humora, M. J., Xu, L., Rohde, E., Gan, L., Jung, M. Y., Shackett, M. N., Chollate, S., Dunah, A. W., Snodgrass-Belt, P. A., Arnold, H. M., Taveras, A. G., Rhodes, K. J., & Scannevin, R. H. (2011). Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator. ACS medicinal chemistry letters, 2(10), 786-91. https://doi.org/10.1021/ml200175q
Peng, Hairuo, et al. "Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator." ACS medicinal chemistry letters vol. 2,10 (2011): 786-91. doi: https://doi.org/10.1021/ml200175q
Peng H, Talreja T, Xin Z, Cuervo JH, Kumaravel G, Humora MJ, Xu L, Rohde E, Gan L, Jung MY, Shackett MN, Chollate S, Dunah AW, Snodgrass-Belt PA, Arnold HM, Taveras AG, Rhodes KJ, Scannevin RH. Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator. ACS Med Chem Lett. 2011 Aug 05;2(10):786-91. doi: 10.1021/ml200175q. eCollection 2011 Oct 13. PMID: 24900267; PMCID: PMC4018072.
Copy Download .nbib Format: NLM
Share it on

ACS Med Chem Lett. 2011 Aug 05;2(10):786-91. doi: 10.1021/ml200175q. eCollection 2011 Oct 13.

Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator.

ACS medicinal chemistry letters

Hairuo Peng, Tina Talreja, Zhili Xin, J Hernan Cuervo, Gnanasambandam Kumaravel, Michael J Humora, Lin Xu, Ellen Rohde, Lawrence Gan, Mi-Young Jung, Melanie N Shackett, Sowmya Chollate, Anthone W Dunah, Pamela A Snodgrass-Belt, H Moore Arnold, Arthur G Taveras, Kenneth J Rhodes, Robert H Scannevin

Affiliations

  1. Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.

PMID: 24900267 PMCID: PMC4018072 DOI: 10.1021/ml200175q

Abstract

We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aβ42, increased Aβ38, but had little to no effect on Aβ40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aβ42 levels in CF-1 mice and Fischer rats, as well as plasma Aβ42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.

Keywords: Alzheimer's; GSM; Mannich reaction; Secretase; amyloid

References

  1. Bioorg Med Chem Lett. 2010 Jan 15;20(2):755-8 - PubMed
  2. J Clin Invest. 2003 Aug;112(3):440-9 - PubMed
  3. Mol Cell Biol. 1998 Dec;18(12):7423-31 - PubMed
  4. Cell. 2005 Feb 25;120(4):545-55 - PubMed
  5. Br J Pharmacol. 2009 Mar;156(6):982-93 - PubMed
  6. Toxicol Sci. 2004 Nov;82(1):341-58 - PubMed
  7. J Biol Chem. 2004 Mar 26;279(13):12876-82 - PubMed
  8. Nature. 2001 Nov 8;414(6860):212-6 - PubMed
  9. Neuron. 2005 Jul 21;47(2):191-199 - PubMed
  10. Nat Rev Drug Discov. 2010 May;9(5):387-98 - PubMed
  11. Science. 2002 Jul 19;297(5580):353-6 - PubMed
  12. Nat Rev Neurol. 2010 Feb;6(2):99-107 - PubMed
  13. Neuron. 2004 Sep 30;44(1):181-93 - PubMed
  14. Nat Med. 2008 Aug;14(8):837-42 - PubMed
  15. J Med Chem. 2011 Feb 10;54(3):669-98 - PubMed
  16. Biochemistry. 1993 May 11;32(18):4693-7 - PubMed

Publication Types