Identification of 7 Nicotinic Acetylcholine Receptor Agonists for their Assessment in Improving Cognition in Schizophrenia - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 344

binding, hERG functional assessment, CNS penetration in mice, in vivo rat
clearance, and oral bioavailability. 20,26 Several compounds showed potent
( o 250 nM) binding to 5-HT 3 , including 18b, 18c, 19f, 20a, and 21a, but they
were later determined to be antagonists of 5-HT 3 , as was PNU-282987.
In vitro cardiovascular safety was evaluated in a patch-clamp hERG K 1 ion
channel assay. 33 Given the ecacious free plasma concentration of PHA-
543613 in the P50 auditory gating assay, 45 the goal for a backup was to identify
compounds with r 30% inhibition of hERG at 20 mM. A number of analogs
met this criterion, such as 18e, 19a, 19f, 21a, and 21f; however, several analogs,
including those with a benzothiophene (i.e., 18b, 65%) or a pyrrolopyrimidine
(i.e., 18c, 71%), displayed significant hERG activity as expressed as a percent
inhibition at 20 mM. In addition, analogs derived from azabicyclic ring 20
displayed higher hERG activity than that of the other amines. In general, these
data suggested that increased hERG activity for type 18-22 compounds cor-
related with increases in lipophilicity (clog P). For instance, azabicyclo[2.2.1]-
heptane 19a, with a clog P of 2.1, showed lower hERG activity compared to
that of azabicyclo[3.2.2]nonane 20a, with a clog P of 2.6. Significant increases
in hERG activity were seen in compounds with a polarizable atom, such as
benzothiophene 18b. A correlation with pK a was also observed in that more
basic compounds tended to show higher hERG activity (data not shown).
These observations are consistent with descriptors that have now appeared in
the literature to modulate hERG activity for a given chemical series. 46
Compounds lacking a hERG signal were evaluated in a constant-infusion rat
PK model, and the majority of azabicyclic aryl amides demonstrated moderate
to low clearance and later showed good oral bioavailability. 20,27,44 Although
there was no overall relationship to structure, the in vivo clearance and oral
bioavailability (F) reasonably correlated with the in vitro RLM data, where 18e
and 22f had the lowest clearance and 21f had the highest (72mLmin 1 kg 1 ).
The high clearance of 18e and 21f in rats was not a concern, however, as these
compounds were stable in an HLM assay (half-life 4120min). 20,27 As stated
earlier, this trend was seen for many of the aryl bicyclic amides, including PHA-
543613. Indeed, based on the human PK for PHA-543613, RLM appears to
overestimate human systemic clearance for this class of compounds. 47
CNS penetration was accessed for these analogs using a mouse brain uptake
assay. 36 All compounds had robust uptake at either 5 or 60min, and several
(18a, 18d, 19a, 22a) demonstrated a modest degree of CNS accumulation. 27,44
In particular, several analogs in the benzofuran series had significant accu-
mulation, whereas the furanopyridines (PHA-543613, 18f, 21a, 22f) maintained
high CNS penetration without accumulation.
15.4.3 Understanding Reactive Metabolite Profiles
The benzofuran series had always been of some concern owing to the known
metabolic liabilities of furans and benzofurans. The other positive properties of
these compounds directed the team to fully understand any potential risk