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 170

To facilitate the process of obtaining PDE5 co-crystal structures, we also had
a standard operating procedure that enabled rapid soaking of new inhibitors
and provision of high-resolution structures in a 24-hour period. Our intention
was to use this readily available binding information for newly discovered
inhibitors to assess series potential and, where appropriate, to guide potency
and selectivity tuning. The latter was supported by homology models of the
catalytic sites of each of the PDE isoforms (PDEs 6, 10, 11) closest in sequence
similarity to PDE5.
8.3 Medicinal Chemistry Strategy
Despite the wealth of chemical literature in the PDE5 field, 16 we felt that no
current chemotype had the selectivity and physicochemical profile that we
required. In seeking a new inhibitor series, we were encouraged by the struc-
tural diversity amongst literature PDE5 inhibitors and the knowledge that
active-site binding was not restricted to one binding mode. As a result, we
undertook a high-throughput screen (HTS) of the Pfizer compound file. In
assessing the hit matter that emerged, we set out to utilise our PDE structural
knowledge, together with parallel chemistry, in order to accelerate progress and
allow rapid optimisation.
Additionally, we proposed a set of key property criteria, designed to give
confidence that any new emerging chemical lead series would have the cap-
ability of providing a clinical candidate with the desired highly PDE5-selective
and once-daily dosing profile. This strategy would contrast with the sildenafil
programme, wherein the required physicochemistry was pursued after the
active pharmacophore had been discovered. These lead criteria principally
comprised potency/selectivity (PDE5 IC 50 o 50 nM and 410-fold selective over
all other PDEs), physicochemistry (MW o 400, clog P o 4, log D ¼ 1-2) and
absorption/metabolism (ADME) components (well fluxed, predicted human
half-life 412 h), together with wide chemical scope. These criteria were used to
track progress during the hit-to-lead phase and throughout the subsequent lead
optimisation programme. Ligand eciency (LE) 17,18 and ligand lipophilicity
eciency values (LLE) 19,20 were used to aid the hit and lead assessment process.
Binding free energy for LE was calculated from -RT ln K eq using PDE5 IC 50 ,as
the surrogate for dissociation constant and RT equal to 1.4. LLE reflects the
minimally acceptable lipophilicity per unit of in vitro potency, giving an indi-
cation of specific hydrophobic binding requirement and was calculated from -
ln K eq minus clog P with dissociation constant defined as for LE.
8.4 Hit and Lead Optimisation
8.4.1 Diaminoquinazoline Hit Follow-up Strategy
A series of diaminoquinazoline-based hits were identified from high-through-
put screening and displayed a number of positive attributes that encouraged