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 339

Figure 15.6

hERG potassium channel concentration response profiles of PNU-
282987 and 11. Reproduced with permission of the American Chemical
Society from J. Med. Chem., 2006, 49, 4425.

indazole 8. Compound metabolic stability was also assessed using HLM (half-
life 4120min) and revealed moderate stability for 6 and robust stability for 8
and 11. 34
To assess blood-brain barrier penetration, the three compounds were eval-
uated in a multidrug resistance (MDR) P-glycoprotein (PgP) assay. 35 Com-
pounds that show PgP eux, as evidenced by an MDR ratio 43, tend to have
hindered brain penetration. Benzothiazole 6 showed significant PgP eux
(MDR ratio ¼ 13); indazole 8 and furopyridine 11 showed no significant PgP
e ux. CNS penetration was further assessed in a mouse brain uptake assay. 36
Compounds 8 and 11 showed good to excellent brain penetration, but brain
penetration was hindered in benzothiazole 6, which was consistent with its high
MDR eux ratio. The PK and CNS penetration data clearly differentiated
furopyridine 11 (PHA-543613) from benzothiazole 6 and indazole 8, justifying
further in vivo evaluation. 37
The functional activity of PHA-543613 was confirmed using native a7
nAChRs of rat hippocampal neurons. 20 Using a whole-cell patch-clamp con-
figuration on neurons, PHA-543613 evoked desensitizing inward currents that
were concentration dependent and completely inhibited by selective a7 nAChR
antagonist MLA (10 nM). These results suggested that PHA-543613 was
modestly more active than PNU-282987 at native a7 nAChRs, which is con-
sistent with the increased potency, demonstrated in both the binding and the
FLIPR assays using the a7/5-HT 3 chimera (Figure 15.7).
With significant interest in PHA-543613 as a clinical candidate, we sought to
evaluate this compound fully using the battery of in vivo models we had
established for the a7 nAChR program. PHA-543613 was thus tested in the
validated rodent model of impaired sensory gating in which we had previously
achieved proof of concept with PNU-282987. 23,38 Administration of the a7