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.
Zimmermann
Kurt
K
Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA. Kurt.Zimmermann@bms.com
Wittman
Mark D
MD
Saulnier
Mark G
MG
Velaparthi
Upender
U
Langley
David R
DR
Sang
Xiaopeng
X
Frennesson
David
D
Carboni
Joan
J
Li
Aixin
A
Greer
Ann
A
Gottardis
Marco
M
Attar
Ricardo M
RM
Yang
Zheng
Z
Balimane
Praveen
P
Discenza
Lorell N
LN
Vyas
Dolatrai
D
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