Sulfonamide derivatives of bridgehead substituted bicyclo[4.2.1]nonanes as gamma-secretase inhibitors.
Bridgehead substituted derivatives of bicyclo[4.2.1]nonanes were synthesized and shown to be potent inhibitors of gamma-secretase. Two related series were synthesized to explore the SARs. More potent compounds were found in the non-benzofused series compared with the benzofused series. One compound from each series showed good exposure in the hepatic portal vein (HPV) following oral dosing to rats.
Sparey
Tim
T
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. tim_sparey@merck.com
Clarke
Earl
E
Hannam
Joanne
J
Harrison
Timothy
T
Madin
Andrew
A
Shearman
Mark
M
Sohal
Bindi
B
D000284:Administration, Oral; D000473:Alkanes / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D011169:Portal Vein / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
D000473:Alkanes; D001643:Bridged Bicyclo Compounds; D011480:Protease Inhibitors; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases; C017573:nonane