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 85

Table 4.8 Plasma concentration-time course for parent compound 18 and
M þ 16 metabolite following a single oral dose of 100mg kg 1 of
compound 18 in the female nu/nu-CD-1 mouse.

Compound Time (h) Plasma concentration (mM)

18 1 8.19

4 4.62

8 7.95

16 2.64

M þ 16 metabolite 1 11.3

4 8.99

8 11.4

16 5.80

Table 4.9 In vitro profile of PQIP and AQIP including inhibition of pIGF-1R
(enzymatic and mechanistic), CYP3A4 IC 50 , and microsomal
stability.
IGF-1R inhibitor PQIP AQIP

IGF-1R IC 50 (mM) Enzyme 0.024 0.035

Cell (3T3/huIGF-1R) 0.019 0.020

CYP3A4 IC 50 (mM) 8.30 420.0

Microsomal stability (ER) Human 0.59 0.28

Mouse 0.53 0.52

Rat 0.21 0.70

Dog 0.50 0.42

Along these lines, a series of C3-substituted cyclobutyl analogs were synthe-
sized, from which advanced leads PQIP and AQIP emerged (Figure 4.5). 35-37
Both PQIP and AQIP displayed improved potency and microsomal meta-
bolic stability (as noted by lower ERs) (Table 4.9), and the latter translated into
lower in vivo clearance and good oral bioavailability in both mice and rats (and
dogs, data not shown) (Table 4.10). Despite these positive drug-like attributes
associated with both PQIP and AQIP, in mouse and rat models, both com-
pounds displayed a low C max and high V ss . The high V ss associated with these
basic analogs results in the need for relatively high doses to achieve ecacious
plasma levels, and these high doses combined with relatively long half-lives
increase the risk of accumulation and toxicity upon subacute or chronic dosing.
Upon further structural examination of the PQIP and AQIP series, we noted a
trend where the high V ss , long t 2 , and low clearance was associated with the
basic moiety at C3 of the cyclobutyl ring. As a result, we focused efforts on
further exploring the effect of non-basic substituents at C3 of the cyclobutyl
ring, including a series of C3 cyclobutyl alcohols. Those studies led to the
evaluation of the cis-andtrans-secondary alcohols as well as a series of tertiary
cyclobutyl alcohols, 38 from which the tertiary alcohol OSI-906 (Figure 4.6)
emerged as the best in the series based upon multiple factors, including potency,
ecacy, physical properties, and overall ADME/DMPK properties.