The synthesis and SAR of 2-amino-pyrrolo[2,3-d]pyrimidines: a new class of Aurora-A kinase inhibitors.
A new class of Aurora-A inhibitors have been identified based on the 2-amino-pyrrolo[2,3-d]pyrimidine scaffold. Here, we describe the synthesis and SAR of this novel series. We report compounds which exhibit nanomolar activity in the Aurora-A biochemical assay and are able to inhibit tumor cell proliferation. This study culminates in compound 30, an inhibitor with potent activity against Aurora A (IC50=0.008 microM), anti-proliferative activity against several tumor cell lines and induces polyploidy in H460 cells.
Moriarty
Kevin J
KJ
Johnson and Johnson, PRDUS, LLC, Spring House, PA 19477, USA. kevinjmoriarty@comcast.net
Koblish
Holly K
HK
Garrabrant
Thomas
T
Maisuria
Jahanvi
J
Khalil
Ehab
E
Ali
Farah
F
Petrounia
Ioanna P
IP
Crysler
Carl S
CS
Maroney
Anna C
AC
Johnson
Dana L
DL
Galemmo
Robert A
RA
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases