J . Med. Chem. 2001, 44, 1025-1027
1025
some of the side effects noted with sildenafil use.
Consistent with this hypothesis is the fact that the
incidence of side effects is dose-related. The visual
disturbances associated with sildenafil treatment can
be linked to inhibition of PDE6, the sole cGMP PDE in
the retina. Other side effects may be due, at least in
part, to nonspecific inhibition of PDE1, which is abun-
dant throughout most of the vasculature. Thus, more
selective PDE5 inhibitors should be of substantial
clinical interest.5 This communication describes the
discovery of a novel series of pyrazolopyridine deriva-
tives which are potent, selective, efficacious, and orally
bioavailable PDE5 inhibitors.
Resu lts a n d Discu ssion . Compound 2 (Chart 1,
PDE5 IC50 ) 1 nM) was reported as a potent PDE5
inhibitor by Kumar and Dority from Sanofi-Winthrop.6
Using 2 as a template for a substructure search, we
chose a series of pyrazolopyridines for PDE5 screening.
This effort identified 4 (Chart 1, PDE5 IC50 ) 180 nM)
as a nonselective PDE5 inhibitor with modest potency.
Exploration of the SAR of 4 was then initiated using
parallel synthesis (Scheme 1). By varying the amine
substituent located at C4 of the pyrazolopyridine het-
erocycle, we identified 3-chloro-4-methoxyphenylmethyl-
amine (10) as the optimal amine for PDE5 inhibitory
potency. Watanabe and co-workers have made a similar
observation in a series of phthalazines (e.g., 3, Chart
1).7 A second round of parallel synthesis was undertaken
to examine the role of the amide at C5 (Scheme 1). Using
6 as the template, a large library of amides was
synthesized (Scheme 1). This effort afforded many
potent and selective PDE5 inhibitors, as exemplified by
5, with PDE5 IC50’s < 10 nM. The best PDE5 selectivity
profiles were found in those amides which contained
hydrogen-bonding functionalities, such as pyridines (5),
phenols, ethers (7), esters, alcohols (8), and amides (9)
(Chart 1).10
Among the compounds in the above-described amide
library, compound 5 distinguished itself based on physi-
cal properties (such as solubility) and in vitro biological
properties (Table 1).8 The potency and selectivity of 5
were much improved compared to sildenafil (1). Most
notable was the significantly improved selectivity for
PDE5 versus PDE6 and PDE1.
The ability of a compound to potentiate relaxation of
corpus cavernosal tissue strips in vitro has been used
as a functional measure of the PDE5 inhibition.9 This
model requires that the drug penetrates corpus caver-
nosal cells, since PDE5 is an intracellular enzyme.
When evaluated in rabbit corpus cavernosal tissue
strips, 5 demonstrated equal efficacy compared to
sildenafil (1, Table 2). Thus, in addition to being a more
potent and selective PDE5 inhibitor in vitro (compared
with sildenafil), compound 5 was at least equivalent to
sildenafil in its functional PDE5 activity in rabbit corpus
cavernosal tissue.
Su bstitu ted P yr a zolop yr id in es a s P oten t
a n d Selective P DE5 In h ibitor s: P oten tia l
Agen ts for Tr ea tm en t of Er ectile
Dysfu n ction
Guixue Yu,*,† Helen J . Mason,† Ximao Wu,†
J ian Wang,‡ Saeho Chong,‡ Gary Dorough,§
Andrew Henwood,§ Ronald Pongrac,# Laurie Seliger,#
Bin He,# Diane Normandin,# Leonard Adam,#
J ohn Krupinski,# and J ohn E. Macor†
Discovery Chemistry, Drug Metabolism and
Pharmacokinetics, Drug Safety, and Metabolic &
Cardiovascular Drug Discovery, Bristol-Myers Squibb
Pharmaceutical Research Institute, P.O. Box 5400,
Princeton, New J ersey 08543-5400
Received J anuary 18, 2001
In tr od u ction . Erectile dysfunction (ED) was largely
an unmet medical need prior to the introduction of
sildenafil [Viagra (1), Chart 1] in 1998.1 Sildenafil is a
potent inhibitor of phosphodiesterase type 5 (PDE5),2
and it was originally studied for the treatment of angina
before its effectiveness in treating ED was serendipi-
tously discovered. Despite its success, sildenafil has
several notable side effects such as headache, nausea,
cutaneous flushing, and visual disturbances.2a,3 These
side effects may be attributed to the limited selectivity
of 1 against other PDE isozymes, most notably PDE1
and PDE6 (Table 1). Thus, the need exists for improved
PDE5 inhibitors possessing greater PDE isozyme se-
lectivity and demonstrating fewer side effects. In this
Letter, we detail a new series of potent PDE5 inhibitors
represented by 5, which have a much improved PDE
isozyme selectivity profile compared to 1.
PDE5 is a member of the phosphodiesterase family
of enzymes which are responsible for the hydrolysis of
cGMP and/or cAMP.3 PDE5 is the primary cGMP
hydrolyzing enzyme present in the corpus cavernosum,
the tissue in the penis which is engorged with blood
during an erection. Upon sexual stimulation, nitric oxide
(NO) is released from nonadrenergic, noncholinergic
neurons in the penis. NO activates guanylyl cyclase,
which in turn produces cGMP. cGMP initiates a protein
phosphorylation cascade, which causes a decrease in
intracellular calcium within corpus cavernosal smooth
muscle cells, resulting in vasorelaxation, inflow of
arterial blood, and an erection.4 Inhibition of PDE5
increases the effective concentration of cGMP in the
corpus cavernosum, enhancing the above-described ef-
fects.
The therapeutic benefit of sildenafil in ED results
from its potent inhibition of PDE5. However, it is only
modestly selective toward other PDE isoforms, notably
PDE1 and PDE6 (Table 1). At relevant therapeutic
doses of sildenafil, it is likely that measurable inhibition
of PDE1 and PDE6 occurs. This may be the cause of
Examination of the pharmacokinetic profile of 5 in
rats (21 µmol/kg) and dogs (23 µmol/kg) demonstrated
equal or better exposure of drug in rats and dogs
compared with 1 (Table 2). The relatively short terminal
half-life of 5 in both species was well-suited for the on-
* To whom correspondence should be addressed. Tel: 609-818-6528.
Fax: 609-818-3450. E-mail: guixue.yu@bms.com.
† Discovery Chemistry.
‡ Drug Metabolism and Pharmacokinetics.
§ Drug Safety.
#
Metabolic & Cardiovascular Drug Discovery.
10.1021/jm0155042 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/06/2001