Chemistry and Structure Activity Relationships

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Sildenafil (6) is a pyrazolopyrimidinonederiv-ative. The pyazolopyrimidinone ring is essential for PDE5 inhibitory activity. It seems that this ring structure mimics the guanosine base of cGMP (149). Another ring system that has been shown to produce potent and selective PDE5 inhibitory activity is imidazoquinazoli-

(6) Sildenafil Citrate

none (150). In the sildenafil series, the n-pro-pyl substitution on position 3 of the pyazolopy-rimidinone ring gives a more potent compound compared with a 3-methyl analog. Intramolecular hydrogen bonding of sildenafil and its analogs is important for biological activity by maintaining co-planarity between the phenyl and purine ring (151). The 2'-alkoxy moiety on the phenyl group serves this purpose by providing the oxygen lone pair for hydrogen bonding with the pyrimidinone NH (149). The alkoxy moiety also provides the requirement for a small lipophilic substituent, which is important for activity. Replacement of the alkoxy moiety with a hydrogen reduced PDE5 affinity by 200-fold (149). Hydroxy, nitro, and sulphonamide derivatives also had lower affinity to PDE5. It has been demonstrated that an open chain 2'-alkoxyl group serves the li-pophilicity requirement better than a fused ring system. An ether ring fused into the phe-nyl moiety, although increasing the degree of co-planarity, largely reduced the PDE5 inhibitory activity (151). An N-acylamido substitution at the 5'-position of the phenyl ring was shown to enhance PDE5 inhibitory activity (152).Sildenafil analogs with such a substituent were one to three times more potent than sildenafil, based on in vitro PDE5 inhibitory activity. The activity increased with increasing the chain length of the N-acylamido moiety. This substitution, however, decreased the analogs' selectivity to PDE5 over PDE6 (152). The sulfonamide substituent on position 5' enhances the aqueous solubility of sildenafil and also increases its affinity to cGMP (149). Introduction of a carboxylic acid group to the

5'-sulfonamide moiety of the phenyl ring greatly enhanced the in vitro PDE5 activity (153), possibly caused by mimicking the phosphate group of cGMP.

Alprostadil (7) is a synthetic form of prostaglandin Ex (PGEj). It is chemically identical

(7) Alprostadil

to the naturally occurring PGE^ Prostaglandin E1 is an acidic lipid that is synthesized by mammalian tissues from fatty acid precursors.

Yohimbine (8)i s a natural alkaloid found in Rubaceae and related trees, mainly, from the

(8) Yohimbine

bark of the African tree Pasinystalia yohimbe, and is also found in Rauwolfia Serpentina. It is an indolalkylamine alkaloid with structural similarity to reserpine. Chemically, it is known as 17a-hydroxy-yohimban-16a-carboxylic acid methylester. The commercial product contains the hydrochloride salt of yohimbine.

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