title: (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): a potent and highly selective cathepsin K inhibitor for the treatment of osteoarthritis.
abstract: Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
authors: AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. al.dossetter@astrazeneca.com
authors: Alexander G
authors: AG
authors: Dossetter
authors: Howard
authors: H
authors: Beeley
authors: Jonathan
authors: J
authors: Bowyer
authors: Calum R
authors: CR
authors: Cook
authors: James J
authors: JJ
authors: Crawford
authors: Jonathan E
authors: JE
authors: Finlayson
authors: Nicola M
authors: NM
authors: Heron
authors: Christine
authors: C
authors: Heyes
authors: Adrian J
authors: AJ
authors: Highton
authors: Julian A
authors: JA
authors: Hudson
authors: Anja
authors: A
authors: Jestel
authors: Peter W
authors: PW
authors: Kenny
authors: Stephan
authors: S
authors: Krapp
authors: Scott
authors: S
authors: Martin
authors: Philip A
authors: PA
authors: MacFaul
authors: Thomas M
authors: TM
authors: McGuire
authors: Pablo Morentin
authors: PM
authors: Gutierrez
authors: Andrew D
authors: AD
authors: Morley
authors: Jeffrey J
authors: JJ
authors: Morris
authors: Ken M
authors: KM
authors: Page
authors: Lyn Rosenbrier
authors: LR
authors: Ribeiro
authors: Helen
authors: H
authors: Sawney
authors: Stefan
authors: S
authors: Steinbacher
authors: Caroline
authors: C
authors: Smith
authors: Madeleine
authors: M
authors: Vickers
mesh_terms: D000818:Animals; D002243:Carbolines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004285:Dogs; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008297:Male; D008958:Models, Molecular; D010003:Osteoarthritis / Q000188:drug therapy* / Q000201:enzymology; D011480:Protease Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D051381:Rats; D013379:Substrate Specificity
chemical_list: D002243:Carbolines; D007211:Indoles; C575446:N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido(4,3-b)indole-2-carbonyl)cyclohexanecarboxamide; D011480:Protease Inhibitors; D056657:Cathepsin K