•
`
`Pergamon
`
`Bioorganic & Medicinal Cumistry Leners, Vol. 6, No. 15, pp. 1819-1824, 1996
`Copyright Q 1996 Elsevier Science Ltd
`Printed in Great Britain. All rights teserVed
`0960-894X/96 $15.00 + 0.00
`
`PII: S0960-894X(96)00323-X
`
`SILDENAFIL (VIAGRA ™), A POTENT AND SELECTIVE INHffiiTOR OF TYPE 5
`CGMP PHOSPHODIESTERASE WITH UTILITY FOR THE TREATMENT OF
`MALE ERECTILE DYSFUNCTION
`
`Nicholas K. Terrett,* AndrewS. Bell, David Brown1 and Peter Ellis,*
`
`Departments of Discovery Chemistry and Discovery Biology, t
`Pfizer Central Research, Sandwich, Kent, CT13 9NJ, UK
`
`Abstract: 5-(2'-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular our preferred compound,
`sildenaf!l (VIAGRA™), discovered through a rational drug design programme, are potent and selective
`inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavemosum.
`Sildenafil is currently in the clinic for the oral treatment of male erectile dysfunction.
`Copyright © 1996 Elsevier Science Ltd
`
`Introduction: Cyclic guanosine monophosphate (cGMP) is the ubiquitous second messenger for those G(cid:173)
`protein coupled receptors activated by endogenous substances such as nitric oxide (NO or EDRF) and atrial
`natriuretic peptide (ANP).
`Intracellular levels of cGMP are controlled by activation of cyclic nucleotide
`cyclases and breakdown by phosphodiesterases (PDE). Specifically, there are a number of PDE isozymes that
`will hydrolyse cGMP to the inactive GMP and thus cGMP levels may be raised by the use of a selective cGMP
`PDE inhibitor. 2 There are at least seven families of PDE3
`, of which three (types 1, 5 and 6) selectively
`5
`to cAMP.4
`hydrolyse cGMP relative
`PDE
`type 5,
`the calcium/calmodulin
`insensitive cGMP
`'
`phosphodiesterase, occurs in lung, platelets and various forms of smooth muscle. 6
`
`We considered that selective inhibitors of PDE type 5 would be attractive targets for the therapy of a range of
`cardiovascular disorders. As a consequence of our work on ANP/ we anticipated that a potent inhibitor would
`have utility in the therapy of hypertension and angina. However, we found that type 5 cGMP PDE is also the
`predominant cGMP hydrolysing activity in the cytosolic fraction from human corpus cavemosum.8 As penile
`erection is mediated by N0,9 and thus cGMP, 10 inhibitors of type 5 PDE improve erection by enhancing
`relaxation of the corpus cavemosal smooth muscle, and thereby have utility for the treatment of male erectile
`dysfunction (impotence). We here report the discovery of sildenaf!l (VIAGRA ™) (X), a potent and highly
`selective inhibitor for the type 5 PDE, that is an orally active treatment for male erectile dysfunction.
`
`Results and Discussion: Prior to our work, very little had been reported on the design, synthesis and
`screening of selective cGMP PDE inhibitors. Zaprinast (I, M&B 22,948), u developed as an anti-allergy agent,
`was one of the first type 5 PDE inhibitors to be reported, albeit only weakly active and a poorly selective
`
`1819
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` DRL - EXHIBIT 1013
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`1822
`
`N. K. TERRETT et al.
`
`As mentioned above, a 5'-substituent on the 2-ethoxyphenyl ring has the potential to fill a space occupied by
`the phosphate of cGMP in the PDE active site. Access to 5' -substituted analogues is synthetically
`straightforward as electrophilic attack occurs selectively at this position and can be effected at a late stage in
`the synthesis, permitting rapid production of many analogues. Additionally, in order to improve the low
`solubility of compound ill (log D = 4.0), we wanted to make analogues with lower lipophilicity. The
`introduction of polar or charged substituents in 5' -sulphonamides (see Figure 5) gave derivatives with lower
`values of log D. These were demonstrated to possess greater solubility, as compared with m and furthermore
`we found clear increases in enzyme affinity (see compounds X (sildenafiJ.), XI, XD, and Xill). Intriguingly, 5'(cid:173)
`substitution of zaprinast with sulphones or sulphonamides enhanced the antiallergic activity of this series, 18
`although it was not clear that this activity was mediated through inhibition of cGMP PDE.
`
`Figure 5 The lipophilicity of 5-(2 '-alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones could be varied by the use
`of polar or charged 5'-sulphonamide substituents. /C50 values are in nanomolar unless otherwise stated, and
`are the mean values of at least 2 determinations.
`0
`Me
`
`E~ HN~:N
`MN~
`y
`
`"Pr
`
`Compound
`
`m
`X
`Sildenafil
`(VIAGRATM)
`XI
`
`XII
`
`xm
`
`R
`
`Structure
`R=
`
`H
`
`S02N l
`~NMe
`1 \
`S02N N \_
`\_ /
`OH
`
`S02NJ--CONH2
`
`1 \
`NH
`S02N
`\_/
`
`ICso (nM)
`PDE 1
`
`PDE3
`
`790
`260
`
`>100~M
`65,000
`
`460
`
`62,000
`
`PDE5
`. (platelet)
`27
`3.6 (platelet)
`3.0 (corpus
`cavernosum)
`1.9
`
`110
`
`34,000
`
`390
`
`>1001J.M
`
`2.1
`
`5.7
`
`LogO
`
`4.0
`2.7
`
`2.0
`
`2.3
`
`1.5
`
`Overall, our results demonstrated that a range of different 5' -substituents are tolerated by PDE type 5, and
`amongst these, sildenafl.l (X) gave an excellent combination of enzyme inhibitory potency, selectivity, solubility
`and in vivo characteristics.
`
`The synthesis of pyrazolo[4,3-d]pyrimidin-7-ones commenced with the preparation of the pyrazole ring from
`the diketoester (1) and hydrazine (see Figure 6). Following the regioselective N-methylation of the pyrazole,
`hydrolysis gave the carboxylic acid (3). Nitration followed by carboxamide formation and nitro group
`
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