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 88

cis/trans-(hydroxymethyl)cyclobutyl isomers. This cis/trans mixture was treated
with ammonia/isopropanol in a Parr reactor at 110 1C to displace the 8-chloro
group, followed by tosylation of the primary alcohol to afford the cis/trans
mixture of tosylates. At this stage, the isomers were readily separable by silica
gel chromatography and treatment of the cis-tosylate with azetidine afforded
AQIP. For the synthesis of PQIP, compound 26 was converted to cyclobuta-
none derivative 27 via osmium tetraoxide-mediated dihydroxylation of the
exocyclic alkene moiety followed by sodium periodate oxidative cleavage of the
resulting diol. Cyclobutanone 27 was subjected to reductive amination with N-
methylpiperazine followed by NH 3 displacement of the 8-chloro group to
afford PQIP. For the synthesis of OSI-906, reaction of cyclobutanone inter-
mediate 27 with 3MMeMgCl in THF stereoselectively afforded the cis-tertiary
alcohol, which was subsequently treated with ammonia/isopropanol in a
stainless steel Parr apparatus to afford OSI-906 in a yield of 61% over two
steps.

4.8 OSI-906: Biochemical and Cellular IGF-1R
Activity
The mature in vitro through in vivo drug discovery cascade (Figure 4.7) focused
primarily on two cell lines, a 3T3/huIGF-1R cell line (LISN) and a GEO col-
orectal line. 35-37,39,42,43 The LISN line represents an engineered IGF-1R over-
expressing driven mechanism in which signaling pathways and functional
effects of IGF-1R inhibition could be cleanly assessed. The GEO line harbors
an IGF-1R/IGF-2 autocrine loop and therefore represents a naturally occur-
ring IGF-1R ligand-driven tumor line. Moreover, both lines form tumors

Pharmacokinetics (PK)
(Oral)

Biochemical Assay
(ELISA)

Cell Mechanistic (ELISA)
auto-p-IGF-1R:
LISN (NIH-3T3/huIGF-1R cells)
GEO (colorectal cells)

Pharmacodynamics (PD)
(LISN/GEO)

Tumor Growth Inhibition (TGI)
(LISN, GEO, other)

Functional
(Proliferation/apoptosis)

Toxicological and IND-track
enabling Studies

In Vitro ADME

Figure 4.7 General in vitro and in vivo drug discovery cascade.