title: Design of selective, ATP-competitive inhibitors of Akt.
abstract: This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.
authors.affiliation: Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA. kevin.freeman-cook@pfizer.com
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Freeman-Cook
authors.forename: Christopher
authors.initials: C
authors.lastname: Autry
authors.forename: Gary
authors.initials: G
authors.lastname: Borzillo
authors.forename: Deborah
authors.initials: D
authors.lastname: Gordon
authors.forename: Elsa
authors.initials: E
authors.lastname: Barbacci-Tobin
authors.forename: Vincent
authors.initials: V
authors.lastname: Bernardo
authors.forename: David
authors.initials: D
authors.lastname: Briere
authors.forename: Tracey
authors.initials: T
authors.lastname: Clark
authors.forename: Matthew
authors.initials: M
authors.lastname: Corbett
authors.forename: John
authors.initials: J
authors.lastname: Jakubczak
authors.forename: Shefali
authors.initials: S
authors.lastname: Kakar
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Knauth
authors.forename: Blaise
authors.initials: B
authors.lastname: Lippa
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Luzzio
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Mansour
authors.forename: Gary
authors.initials: G
authors.lastname: Martinelli
authors.forename: Matthew
authors.initials: M
authors.lastname: Marx
authors.forename: Kendra
authors.initials: K
authors.lastname: Nelson
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.forename: Francis
authors.initials: F
authors.lastname: Rajamohan
authors.forename: Shaughnessy
authors.initials: S
authors.lastname: Robinson
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Subramanyam
authors.forename: Liuqing
authors.initials: L
authors.lastname: Wei
authors.forename: Martin
authors.initials: M
authors.lastname: Wythes
authors.forename: Joel
authors.initials: J
authors.lastname: Morris
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004285:Dogs; D051379:Mice; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt