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.
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
Tim
T
Sparey
Earl
E
Clarke
Joanne
J
Hannam
Timothy
T
Harrison
Andrew
A
Madin
Mark
M
Shearman
Bindi
B
Sohal
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