title: Novel γ-secretase modulators for the treatment of Alzheimer's disease: a review focusing on patents from 2010 to 2012.
abstract: BACKGROUND
  γ-Secretase is the enzyme responsible for the final step of amyloid precursor protein proteolysis to generate Aβ peptides including Aβ42 which is believed to be a toxic species involved in Alzheimer's disease (AD) progression. γ-Secretase modulators (GSMs) have been shown to selectively lower Aβ42 production without affecting total Aβ levels or the formation of γ-secretase substrate intracellular domains such as APP intracellular domain and Notch intracellular domain. Therefore, GSMs have emerged as an important therapeutic strategy for the treatment of AD.
  
  
  METHODS
  The literature covering novel GSMs will be reviewed focusing on patents from 2010 to 2012.
  
  
  CONCLUSIONS
  During the last review period (2008 - 2010) considerable progress was made developing GSMs with improved potency for lowering Aβ42 levels, but most of the compounds resided in unfavorable central nervous system (CNS) drug space. In this review period (2010 - 2012), there is a higher percentage of potent GSM chemical matter that resides in favorable CNS drug space. It is anticipated that clinical candidates will emerge out of this cohort that will be able to test the GSM mechanism of action in the clinic.
authors.affiliation: Neuroscience Medicinal Chemistry, Pfizer Worldwide Research and Development , 700 Main Street, Cambridge, MA, 02139 , USA doug.johnson@pfizer.com.
authors.forename: Martin
authors.initials: M
authors.lastname: Pettersson
authors.forename: Antonia F
authors.initials: AF
authors.lastname: Stepan
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Kauffman
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010330:Patents as Topic
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D053829:Amyloid Precursor Protein Secretases