The Discovery of OSI-906, a Small-molecule Inhibitor of the Insulin-like Growth Factor-1 and Insulin Receptors - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 79

Table 4.4 IGF-IR biochemical and cell potencies for compounds 15 and 16

O

O

NH 2

NH 2

N

N

N

N

N

N

R 4 R 5

15 16

.

IC 50 (mM)
Biochemical

R 4 /R 5 Cpd

Cell

15a CONH 2 0.221 0.898

15b CONHMe 0.105 1.72

15c CH 2 NH 2 0.119 0.534

15d CH 2 NEt 2 0.115 0.440

15e CH 2 -azetidinyl 0.081 0.398

15f CH 2 -pyrrolidinyl 0.103 0.547

15g CH 2 -morpholino 0.091 0.651

16a CH 2 NH 2 0.060 0.690

16b CH 2 NMe 2 0.166 0.191

16c CONH 2 0.554 2.08

Table 4.5 Mouse iv and oral pharmacokinetics for compounds 1a, 15a, 15b,
and 15c.

Compound 1a 15a 15b 15c

iv
Dose (mg kg 1 ) 1.00 1.00 5.00 1.00

t 1/2 (h) 1.30 1.30 3.15 2.29

V ss (L kg 1 ) 11.50 4.02 4.57 9.58

Cl (mLmin 1 kg 1 ) 221 215 116 93

Oral
Dose (mg kg 1 ) 50.0 50.0 50.0 50.0

C max (mM) 0.86 2.22 4.15 2.85

AUC 0 N (ng hmL 1 ) 1756 1323 3666 3926

Oral bioavailability (%F) 47 34 51 47