A Case History on the Challenges of Central Nervous System and Dual Pharmacology Drug Discovery - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 274

made as an intermediate for a d-opioid ligand program, but possessed inter-
esting levels of monoamine reuptake activity. 32
During SAR investigations of this series, piperazine 10 was discovered which
possessed excellent in vitro pharmacology 32 and, despite its high clog P, it was
highly selective against other GPCR targets when screened at CEREP. How-
ever, piperazine 9 did possess potent activity against a range of ion channels, in
particular Na channels (site 2, IC 50 ¼ 410 nM) and Ca channels (L-type, dil-
tiazem site, IC 50 ¼ 730 nM). To determine the impact of this in vitro ion channel
activity, compound 10 was assessed in a conscious dog cardiovascular study. A
complex haemodynamic profile emerged for compound 10, primarily involving
changes in heart rate and contractility with only a moderate therapeutic index
between projected ecacious free drug levels in human and cardiovascular side
effects and so further development of this compound was halted. We felt that
the high clog P of 10 was a major contributing factor to its ion channel activity
and therefore sought to reduce clog P in this series whilst maintaining SNRI
activity. Unfortunately, as with the pyridyl phenyl ethers above, there was a
clear relationship between clog P and NA activity and none of the more polar
piperazine analogues that were synthesised possessed the correct balance of
SNRI potency and other key properties such as weak P450 inhibition.
At this stage we chose to investigate the role of the piperazine ring and a
scaffold-hopping exercise to an aminopyrrolidine template was carried out. 33
This was guided by synthetic expedience rather than any specific SAR
hypothesis, as suitably protected enantiomerically pure 3-aminopyrrolidine
starting materials were commercially available. This small change in structure
brought about a significant change in the potency/lipophilicity relationship,
which can be seen graphically in Figure 12.7. Now, a significant number of
analogues had combined clog P values o 3.5 and NA potency o 50 nM,
whereas very few piperazine analogues combined those properties.
Among the compounds synthesised in the aminopyrrolidine series, the tet-
rahydropyranyl analogue 11 was profiled extensively. The combination of
SNRI potency with significantly reduced ion channel activity, when compared
to the piperazine analogue 10, made 11 an exciting new lead (Figure 12.8).
However, when the metabolic profile of 11 was investigated in in vitro
microsomal preparations, it was discovered that 11 was predominantly meta-
bolized by CYP2D6 (480%) via oxidation of the benzylic ring and to a lesser
degree by CYP3A4 via dealkylation (Figure 12.8). Predominant metabolism of
a drug via CYP2D6 can result in either significantly increased or decreased
exposure levels in different patient groups. For example, there is a risk of sig-
nificant over-exposure of 11 in poor metabolisers (patients who have mutations
in their CYP2D6 genes which result in reduced CYP2D6 activity) or under-
exposure in ultra-rapid metabolisers (patients who have multiple copies of the
CYP2D6 gene which results in increased CYP2D6 activity), relative to expo-
sure observed in extensive metabolisers (patients with normal levels of CYP2D6
activity). 34 Based on this finding, it was decided to halt the progression of
compound 11. Blocking the CYP2D6 oxidation pathway of 11 through judi-
cious modification of the benzylic substituent was successful, as illustrated by