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 334

N

MeO OMe

O

O

O

N Cl

N

H

H NH

N

N
Anabasine

N

N

O

GTS-21

AR-R17779

N 1

Nicotine

Figure 15.1 a7 nAChR agonists.

template. 15 More generally, 1 is a member of the CNS class of the 1,2-diamine-
monoamides that have found utility as modulators of a variety of CNS
receptors.

15.2.2 Using Parallel Medicinal Chemistry to Rapidly Identify
Leads
Because few selective a7 nAChR agonists were described in the literature in
1998 on which to build a structure-activity relationship (SAR), parallel
synthesis was used to explore the potential of this diamine-amide class of
molecules as agonists of the a7 nAChR. 16 The FLIPR assay we had imple-
mented was not only reliable but also provided our program with a robust and
rapid measure of potency and functional activity in a single HTS. To accelerate
hit follow-up and assess whether a7/5-HT 3 selectivity could be attained, we
prepared and tested focused libraries of commercially available 1,3-diamino-
amides, 17 a hit expansion strategy that allowed for swift SAR evaluation. In
addition, we focused on a series with key lead attributes such as ''drugability''
(Lipinski rule of five), structures lacking toxic functionality, nAChR and 5-HT 3
selectivity, good pharmacokinetic (PK) properties, and excellent CNS pene-
tration. The wide availability of amide bond-forming procedures allowed us to
screen a diverse set of substrates (Figure 15.2), which were quickly evaluated
for potency and functional activity in a FLIPR assay that used SHEP cells
expressing the a7/5-HT 3 chimera (Figure 15.2). The resulting libraries showed a
wide range of activity, indicating a general and useful SAR. For the amine it
was clear that the only analogs in this series with potent activity contained the
3-aminoquinuclidine unit, wherein the (R) configuration was preferred over the
(S). It was also apparent that 5-HT 3 selectivity could be attained by substitu-
tion in the 4-position of the aryl ring, whereas substitution in the 2-position
resulted in potent 5-HT 3 activity. The most promising compound that
emerged from the parallel synthesis was 4-chlorobenzamide (C7), PNU-282987
(Figure 15.2), which was potent at the a7/5-HT 3 chimera [half maximal effec-
tive concentration (EC 50 ) ¼ 178 nM] and selective versus 5-HT 3 . 17

15.2.3 Developing a Robust Screening Strategy
With PNU-282987 in hand as a key tool compound, we could develop the full
screening strategy for the program. To understand the in vitro a7 nAChR