The Discovery of the Longacting PDE5 Inhibitor PF-489791 for the Treatment of Pulmonary Hypertension - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 173

Cl

Favoured monomers,
e.g. aminopyridines

Amine 1

R

R

Library 2

N

N

R 1 N Cl

R 1 N Amine 2

Dichloroheterocycle
templates

Influence physicochemsitry,
e.g. pendant basic centre
for volume of distribution
and solubility

Figure 8.6 Design basis for second library.

Table 8.2 In-depth profile of lead compound 3

Me

N

HN

Me

7

1

N

N

N

N N

5

3

nPr

NH

3

.

Criteria Value

PDE5 IC 50 (nM) 71

PDE6 IC 50 (nM) 1330

PDE10 IC 50 (nM) 79

PDE11 IC 50 (nM) 210

All other PDE IC 50 's (nM) 41000

clog P 3.1

MWt 366

LE (PDE5) 0.37

LLE (PDE5) 4.0

A-B ¼ 18 10 6 cm s 1 ,ER o 1

Caco-2 flux

V D ¼ 23 L kg 1 , t 1/2 ¼ 1.4 h

Rat pharmacokinetics

Projected human half-life 412 h

indicated a high volume of distribution that enabled a projected human
half-life of 412 h. A further important advantage that 3 offered was wide
chemical scope, with four substituent positions readily amenable to chemical
modification.