Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer's disease.
BACKGROUND
Alzheimer's disease is thought to be caused by increased formations of neurotoxic amyloid beta (A beta) peptides, which give rise to the hallmark amyloid plaques. Therefore, pharmacological agents that reduce A beta formation may be of therapeutic benefit.


OBJECTIVE
This paper reviews the pharmacology and chemical efficacy of an A beta-lowering agent, semagacestat (LY450139).


METHODS
A review of the published literature pertaining to semagacestat was obtained using several electronic search engines; unpublished data on file at Eli Lilly and Co. were used as supplementary material.


CONCLUSIONS
Semagacestat treatment lowers plasma, cerebrospinal fluid and brain A beta in a dose-dependent manner in animals and plasma and cerebrospinal fluid A beta in humans, compared with placebo-treated patients. On the basis of extant data, semagacestat seems to be well tolerated, with most adverse events related to its actions on inhibition of peripheral Notch cleavage. Thus far, clinical efficacy has not been detectable because of the short duration of the current trials. Phase III trials with 21 months of active treatment are currently underway.
Henley
David B
DB
Eli Lilly and Company, Lilly Corporate Center, Clinical Research Physician, Alzheimer's Team, DC 6161, Indianapolis, IN 46285-6161, USA. henleyda@lilly.com
May
Patrick C
PC
Dean
Robert A
RA
Siemers
Eric R
ER
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003072:Cognition Disorders / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D010829:Physiological Phenomena / Q000187:drug effects; D016032:Randomized Controlled Trials as Topic
D001381:Azepines; D002800:Cholinesterase Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine