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 351

Substitution here =
weak potency

Substitution here = Good potency/efficacy
Cl, Br (1-2 nM) > Me, CN, Ph, OPh (6-7
nM) > F, Et (17 nM)

7 6

Substitution here = Good potency/efficacy
Ph, pyrrolidine ( K i =2-3nM)>Me,Et,OAr(12-20nM)

5

O

N

4

N

N

N

Figure 15.14

Structure-activity relationships of the 4-azabenzoxazole series.

Table 15.2 Pharmacologic profile of four high-interest 4-azabenzoxazole
analogs. 61

Br Ph Cl

O O

O O

N N

N N

N N

N N

N N

N N

N N N N

Compound ID 33 34 35 36

a7 K i (nM) 2.1 13.3 7.0 3.2
% Agonist vs. nic 347% 195% 380% n.d.
a7/5-HT 3 EC 50 (nM, %) 240(64%) 244(46%) 320(71%) 160(58%)
a4b2IC 50 (nM) 771 1,350 >10,000 n.d.
a3b4IC 50 (nM) 180 5,370 n.d. n.d.
5-HT 3 K i (nM) 926 248 2,117 244
5-HT 3 IC 50 (nM) 779 5 n.d. 70
hERGIC 50 (nM) 2,300 40,000 1,700 16,200
In vitro micronucleus Pos Neg Pos Neg
EC 50 , half maximal effective concentration; hERG, human ether-a` -go-go; n.d., not determined; nic,
nicotine; IC 50 , the half-maximal inhibitory concentration; K i , binding anity.

versus 5-HT 3 (19-440 ) and acted as antagonists in a functional assay for the 5-
HT 3 receptor.
With the exception of 35, the compounds in Table 15.2 displayed good
selectivity versus the hERG channel (41000 vs. a7 K i ). An interesting SAR
trend emerged during in vitro micronucleus testing in that 34 and 36 were
negative and 33 and 35 were positive, suggesting that substitution at the 5-
position precludes in vitro genetic toxicity. The overall in vitro potency and
selectivity profiles at a7 nAChR, a4b2 nAChR, a3b4 nAChR, and 5-HT 3 , and
in hERG, and in vitro micronucleus testing along with ease of synthesis (vs. 36)
prompted further evaluation of compound 34 in both in vitro and in vivo
ADME studies and our in vivo ecacy models.