Design of selective, ATP-competitive inhibitors of Akt.
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.
Freeman-Cook
Kevin D
KD
Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA. kevin.freeman-cook@pfizer.com
Autry
Christopher
C
Borzillo
Gary
G
Gordon
Deborah
D
Barbacci-Tobin
Elsa
E
Bernardo
Vincent
V
Briere
David
D
Clark
Tracey
T
Corbett
Matthew
M
Jakubczak
John
J
Kakar
Shefali
S
Knauth
Elizabeth
E
Lippa
Blaise
B
Luzzio
Michael J
MJ
Mansour
Mahmoud
M
Martinelli
Gary
G
Marx
Matthew
M
Nelson
Kendra
K
Pandit
Jayvardhan
J
Rajamohan
Francis
F
Robinson
Shaughnessy
S
Subramanyam
Chakrapani
C
Wei
Liuqing
L
Wythes
Martin
M
Morris
Joel
J
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
D000577:Amides; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt