Balancing oral exposure with Cyp3A4 inhibition in benzimidazole-based IGF-IR inhibitors.
3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via S(N)Ar reaction and double decarboxylation under mild conditions is demonstrated.
Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA. Kurt.Zimmermann@bms.com
Kurt
K
Zimmermann
Mark D
MD
Wittman
Mark G
MG
Saulnier
Upender
U
Velaparthi
David R
DR
Langley
Xiaopeng
X
Sang
David
D
Frennesson
Joan
J
Carboni
Aixin
A
Li
Ann
A
Greer
Marco
M
Gottardis
Ricardo M
RM
Attar
Zheng
Z
Yang
Praveen
P
Balimane
Lorell N
LN
Discenza
Dolatrai
D
Vyas
D000255:Adenosine Triphosphate / Q000737:chemistry; D000284:Administration, Oral; D019540:Area Under Curve; D001562:Benzimidazoles / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D065692:Cytochrome P-450 CYP3A Inhibitors; D015195:Drug Design; D005461:Fluorine / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009584:Nitrogen / Q000737:chemistry; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013002:Somatomedins / Q000737:chemistry; D013936:Thymidine / Q000737:chemistry
D001562:Benzimidazoles; D065692:Cytochrome P-450 CYP3A Inhibitors; D013002:Somatomedins; D005461:Fluorine; D000255:Adenosine Triphosphate; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017526:Receptor, IGF Type 1; D009584:Nitrogen; D013936:Thymidine