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 78

Table 4.3 IGF-IR biochemical and cell potencies for compounds 1a and 14a-m

O

NH 2

R 3

N

N

N

14

.

IC 50 (mM)

R 3 Cpd Biochemical Cell

1a H 0.606 1.16

14a 2-F 0.224 2.06

14b 3-F 0.510 3.29

14c 4-F 1.23 -

14d 2-Cl 0.343 -

14e 3-Cl 2.12 -

14f 4-Cl 0.980 410.0

14g 2-OCF 2 H 3.28 -

14h 3-OCF 2 H 5.78 -

14i 4-OCF 2 H 2.82 -

14j 2-CN 410.0 -

14k 4-CN 410.0 -

14l 3-CHCONH 2 410.0 -

14m 3-NHCOCH 3 410.0 -

cellular IGF-1R kinase IC 50 values of 119 and 534 nM, respectively. In the
cyclobutyl series, the dimethylamino derivative 16b displayed the best balance of
biochemical and cellular potencies, with respective IC 50 values of 166 and
191 nM. Select lead compounds were profiled in mice to gain an early under-
standing of the PK properties associated with this series (Table 4.5). Overall, the
compounds had favorable oral bioavailabilities but displayed clearances
exceeding mouse liver blood flow (490mLmin 1 kg 1 ). Metabolic profiling of
compound 15a revealed two metabolites: hydrolysis of the parent primary
amide to the carboxylic acid and the acyl-glucuronidate metabolite of the acid.
Interestingly, the slightly bulkier methylamide 15b displayed a significantly
lower rate of clearance than the primary amide 15a, which correlated with a
slower rate of metabolic hydrolysis to the acid. Moreover, removal of the amide
altogether to afford aminomethyl derivative 15c resulted in the lowest rate of
clearance amongst these cyclohexyl analogs.
In order to gain insight to the selectivity profile associated with this class of
compounds, a representative compound, 15c, was screened for inhibitory
activity against 15 additional purified protein kinases from the tyrosine and
serine/threonine kinase families. Less than 50% inhibition at 10 mM of the