The Discovery of UK-390957: the Challenge of Targeting a Short Half-life, Rapid T SSRI - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 151

Figure 7.4 Free drug levels of UK-373911 following oral dosing in man.

pre-clinical toxicology studies, and was progressed to first-in-human (FIH)
studies. These studies showed that while we had achieved our target of reducing
T max ( o 2 h) relative to compound 3, we had failed to deliver a compound with
a short half-life. Compound 14 has exceptionally low clearance in man, which
gives it a half-life of 4240 h (Figure 7.4).
In contrast to rat and dog, clearance in man appears to be predominantly
due to CYP-mediated metabolism to the circulating metabolite, primary amine
25 (SRI IC 50 ¼ 50 nM). A retrospective analysis in human liver microsomes
(HLM) showed that monitoring for appearance of the primary amine 25 gives a
good estimate of the low clearance of 14 observed in man.

NH 2

O O

S

H 2 N

Cl

25

Cl

7.4 Optimising an Inherently Lower Volume Template:
Diphenyl Ethers
Although we managed to reduce the V D in the tetrahydronaphthalene template
by introducing polarity and reducing the pK a , we began to realise that our
initial medicinal chemistry strategy of starting with a marketed SSRI was
flawed. While polarity and basicity do affect V D , chemical structure plays a very
important, if poorly understood, role in determining the volume. As the mar-
keted SSRIs represent chemical structures with high V D , it will be inherently