2656 J. Med. Chem. 2010, 53, 2656–2660
DOI: 10.1021/jm901781q
Design, Synthesis, and Biological Evaluation of 3-[4-(2-Hydroxyethyl)piperazin-1-yl]-
7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a Potent,
Orally Active, Brain Penetrant Inhibitor of Phosphodiesterase 5 (PDE5)
Robert O. Hughes,*,† D. Joseph Rogier,† E. Jon Jacobsen,† John K. Walker,† Alan MacInnes,† Brian R. Bond,†
Lena L. Zhang,† Ying Yu,† Yi Zheng,† Jeanne M. Rumsey,† Jennie L. Walgren,† Sandra W. Curtiss,† Yvette M. Fobian,†
Steven E. Heasley,† Jerry W. Cubbage,† Joseph B. Moon,† David L. Brown,† Brad A. Acker,† Todd M. Maddux,†
Mike B. Tollefson,† Brent V. Mischke,† Dafydd R. Owen,‡ John N. Freskos,† John M. Molyneaux,† Alan G. Benson,† and
Rhadika M. Blevis-Bal†
†Pfizer Global Research and Development, Chesterfield Parkway West, St. Louis, Missouri 63017, and ‡Pfizer Global Research and Development,
Ramsgate Road, Sandwich CT139NJ, U.K.
Received December 1, 2009
We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward
optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-
7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an ex-
cellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a
spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will
be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound
has recently entered clinical trials.
Introduction
that of 1. To implement this strategy, we focused on modifica-
tions to the southwest (SW) region of the molecule. As deter-
mined by crystallographic analysis, the SW substituent points
toward the solvent; therefore, modifications to this region of the
molecule would likely have minimal effect on the PDE potency
and selectivity. Herein, we described our efforts to identify a
basic compound from the aminopyridopyrazinone class. These
efforts culminated in the discovery of clinical candidate 13.
We considered the previously described basic compounds 2
and 35 as good starting points worthy of further optimization.
As summarized in Table 1 both compounds demonstrate
excellent potency against PDE5, derived from human plate-
lets, and good selectivity over PDE6 and PDE11. Both
compounds also possessed high (>100 μM) aqueous solubi-
lity. Encouragingly, in the case of the 3, the affinity for the
hERG channel (4.5 μM) was only modest. Unfortunately,
both compounds suffered from high clearance in the rat.
Accordingly, our goal was to improve the pharmacokinetic
profile of this subset of compounds while maintaining the
favorable aspects: potency, selectivity, solubility, and hERG
margin. As illustrated in Figure 2, we speculated that reducing
the flexibility and rotational degrees of freedom in the SW
substituent by constraining it into a ring system (as piperazine
or a homopiperazine) would result in an improvement in
metabolic stability. That is, we hypothesized that positive
impact of the removal of three rotatable bonds from 2 or 3 on
the pharmacokinetic profile of these compounds would out-
weigh any deleterious effects from the slight increase in
lipophilicity of the new molecules.
Gathered over the past decade, significant clinical and
commercial experience has demonstrated the safety, tolera-
tion, and efficacy of PDE5 inhibitors, such as sildenafil,
for the treatment of male erectile dysfunctionon (MEDa).1
Furthermore, experimental studies and clinical trials indicate
that PDE5 inhibitors are effective in the treatment of various
other diseases such as Raynaud’s disease, gastrointestinal
disorders, and stroke and exert cardioprotective effects.2
With this potential in mind and initially targeting the
discovery of compounds suitable for use as antihypertensive
agents, we initiated a program directed toward the discovery
of long-acting, selective inhibitors of PDE5. Previously, we
reported on the identification of the aminopyridopyrazinone
class of PDE5 inhibitors.3 Among the desirable features of
this class of PDE5 inhibitors was the excellent selectivity
over other PDE isoforms.4 Initial optimization of the profile
of this class of compounds led to neutral inhibitor 3-[(trans-4-
hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-
propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one,5 1 (Figure 1),
which possessed an excellent preclinical profile including
robust, sustained reduction in blood pressure (BP) in the
SHR model of hypertension. Upon further study, however,
this compound caused unacceptable toxicity6 whichprecluded
its further development. To overcome this shortcoming, one
strategy that we pursued was to develop compounds from
different physicochemical classes7 in the anticipation that
toxicological profile of these compounds would diverge from
*To whom correspondence should be addressed. Phone: (636) 247-
9303. Fax: (636) 247-5620. E-mail: Robert.O.Hughes@pfizer.com.
a Abbreviations: BP, blood pressure; SHR, spontaneously hypertensive
rat; PDE, phosphodiesterase; MED, male erectile dysfunction; CNS,
central nervous system; PK, pharmacokinetics; SD, Srague-Dawley.
Results and Discussion
The synthetic route into this class of molecules is summar-
ized in Scheme 1. Treatment of 4 with n-BuLi followed by
r
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2010 American Chemical Society