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 80

compound was noted for the following enzymes: Ab1, Cdk2/CyclinA, Cdk2/
CyclinE, Chk2, CK2, c-Raf, Fes, IKK-b, MAPK2, p70S6K, PDGFR-b,
PDK1, PKA, PKBa and PKCa. Inhibition of IR was similar to that observed
for IGF-IR, reflecting the high homology of the IGF-1R and IR ATP binding
domains.
4.6 Series II: Quinolinyl-derived Imidazopyrazine
IGF-1R Inhibitors
The aforementioned medicinal chemistry analoging efforts provided insights
into a novel series of 1,3-disubstituted 8-aminoimidazo[1,5-a]pyrazine IGF-IR
inhibitors. While the BnOC 6 H 4 derivatives such as (aminomethyl)cyclohexyl
and -cyclobutyl analogs 15 and 16, respectively, provided early leads, a sig-
nificant increase in potency and an improvement in drug metabolism and
pharmacokinetic (DMPK) properties were required to afford molecules that
would justify clinical development. A key breakthrough in the program came
with an X-ray co-crystal structure of IR and cyclohexyl analog 15a (Figure 4.3,
panel A). From the co-crystal structure, several key binding determinants were
identified (Figure 4.3, panel B): (1) the 8-amino group and the N7 nitrogen are
making critical hydrogen-bonding interactions with the hinge backbone resi-
dues E1080 and M1082, respectively; (2) the methylene and ether oxygen are
almost completely coplanar with the proximal phenyl ring; (3) the oxygen from
the benzyl ether moiety accepts an H-bond from K1033; (4) a modest hydro-
phobic cavity exists below the proximal phenyl ring and benzylic carbon; (5) the
terminal phenyl ring is buried deep in a hydrophobic pocket, making critical
van der Waals contacts with the DFG motif and F1037 and A1051 from the a-
helix C; (6) the cyclohexyl moiety makes van der Waals interactions with the P-
loop near V1013 and L1005 above the ribose binding pocket; and (7) the
cyclohexyl amide extends into the ribose binding pocket. Based on the identi-
fication of these key binding determinants, structure-based design (SBD) efforts
ensued. Efforts focused on locking the benzyloxyphenyl moiety into the
bioactive conformation via exploiting the near co-planarity between the -O-
CH 2 - and proximal phenyl ring while simultaneously filling the unoccupied
hydrophobic pocket below the proximal phenyl and ether moiety. This was
envisioned to be accomplished through replacing the benzyloxyphenyl moiety
with 2-phenylquinolin-7-yl (Figure 4.3, panels C and D), while maintaining all
other key pharmacophoric elements associated with binding (hinge-binding
motif, substituents occupying the ribose binding pocket, and H-bond acceptor
to K1033 in the form of the quinoline nitrogen). To our delight, the intro-
duction of a constrained quinolinyl moiety to provide compound 17 led to a 20-
fold increase in IGF-1R potency when compared directly to its BnOC 6 H 4
counterpart 15a. Additionally, an overall improvement in oral PK properties
(%F, clearance, C max , and AUC) was observed (Table 4.6). We also learned
that salt form and formulation could play a significant role in influencing oral
bioavailability and exposure. For example, the bis-HCl salt of compound 17,