Timeline of some of the major findings in preclinical and clinical stages of the development of semagasestat. Preclinical data on limitations in efficacy of semagasestat related to aging and initial plaque load (see text) are not included in this scheme. GSI, γ-secretase inhibitor; LY, LY450139 (semagasestat); swe, Swedish mutation; WT, wild type. References: (1) Durkin et al, J Biol Chem, 1999. 274: p. 20499-504; (2) May et al, Neurobiol Aging, 2004. S1: p. S65; (3) Ness et al, Neurobiol Aging, 2004. S1: p. S238; (4) Lily's data on file— for review see Henley et al, Expert Opin Pharmacother, 2009. 10: p. 1657-64; (5) Lanz et al, J Pharmacol Exp Ther, 2006. 319: p. 924-33; (6) Siemers et al, Clin Neuropharmacol, 2005. 28: p. 126-32; (7) Bateman et al, Ann Neurol, 2009. 66: p. 48-54; (8) Siemers et al, Clin Neuropharmacol, 2007. 30: p. 317-25; (9) Siemers et al, Neurology, 2006. 66: p. 602-4; (10) Fleisher et al, Arch Neurol, 2008. 65: p. 1031-8; (11) Portelius et al, Alzheimers Res Ther, 2010. 2: p. 7; (12) Burton et al, J Biol Chem, 2008. 283: p. 22992-3003; (13) Bittner et al, J Neurosci, 2009. 29: p. 10405-9; (14) Siemers, Alzheimer's Association International Conference, 19 July 2011, Paris, France.