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 172

Figure 8.4

(a) Co-crystal structure of a 2,4-diamino-6-nitroquinazoline related to 1
with the catalytic domain of PDE5. H-bonds to GLN817 and GLN775
illustrated, but no ''alkoxy'' pocket interaction. (b) Co-crystal structure of 3
illustrating the GLN817 bidentate H-bond from the aminopyridine motif
and the N1 methyl group sitting at the mouth of the ''alkoxy'' pocket. Solid
renderings to the PDE5 binding site surface are coloured by hydrophobicity.

Me

N

Cl HN

Library 1

N N

R

OMe

N H

N Cl

Dichloroquinazoline
templates

2
PDE5 IC50 255nM
cLogP 3.8, MWt 309
LE 0.4, LLE 2.8

Figure 8.5 Follow-up library based on HTS hit 1 leading to aminopyridine derivative 2.

were identified, the pyrazolopyrimidine 3 stood out. The pharmacology
in terms of PDE5 potency and selectivity against the other PDEs was close
to our lead criteria, whilst the physicochemical and ADME properties were
well inside our target range (Table 8.2). In particular, rat pharmacokinetics