title: Novel acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329).
abstract: Inhibition of 11β-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.
authors.affiliation: Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca Mereside , Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. jamie.scott@astrazeneca.com
authors.forename: James S
authors.initials: JS
authors.lastname: Scott
authors.forename: Joanne
authors.initials: J
authors.lastname: deSchoolmeester
authors.forename: Elaine
authors.initials: E
authors.lastname: Kilgour
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Mayers
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Packer
authors.forename: David
authors.initials: D
authors.lastname: Hargreaves
authors.forename: Stefan
authors.initials: S
authors.lastname: Gerhardt
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Ogg
authors.forename: Amanda
authors.initials: A
authors.lastname: Rees
authors.forename: Nidhal
authors.initials: N
authors.lastname: Selmi
authors.forename: Andrew
authors.initials: A
authors.lastname: Stocker
authors.forename: John G
authors.initials: JG
authors.lastname: Swales
authors.forename: Paul R O
authors.initials: PR
authors.lastname: Whittamore
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008252:Macaca fascicularis; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: C000589241:4-(4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl)benzoic acid; D001565:Benzoates; D004791:Enzyme Inhibitors; D020719:Glucuronides; D011720:Pyrazoles; D011725:Pyridines; C031280:pyrazole; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C023666:pyridine