Sildenafil analogs

Khan KM et al. (2005) A facile and improved synthesis of sildenafil (Viagra) analogs through solid support microwave irradiation possessing tyrosinase inhibitory potential, their conformational analysis and molecular dynamics simulation studies. Mol Divers 9(l-3) 15-26... 

The drug most commonly used in patients who do not respond to sildenafil is alprostadil, a PGEi analog (see Chapter 18) that can be injected directly into the cavernosa or placed in the urethra as a minisuppository, from which it diffuses into the cavernosal tissue. Phentolamine can be used by injection into the cavernosa. These drugs will cause erection in most men who do not respond to sildenafil. 

PGR analog/mimetic (epoprostenol, FR181157) Sildenafil Inhibits platelet aggregation Inhibits type-5 phosphodiesterase and reduces platelet activation... 

Figure 2.9 Already three decades ago, the clinical candidate zaprinast 27 (M B 22, 948) and its sulfonamide analog 28 were synthesized. Whereas 27 is about 40 times more active as an antiallergic agent than the standard compound cromoglycate, 28 has a 1000-fold activity. Sildenafil 29 was originally investigated as an antianginal drug, but turned out to support and maintain penile erections.

As has been demonstrated through X-ray crystallographic analysis [21] with sildenafil (10) and vardenafil (12), the amide moiety forms a bidentate H-bond interaction with Gin 817, analogous to the mode in which the lactam portion of cGMP itself is expected to bind (Figure 9.6). The orientation of the sidechain amide... 

For other small molecules, the mechaiusm of action is still unclear. For example, sildenafil and structural analogs have recently been shown to correct trafficking of deltaF508 CFTR mutants (19, 21). Sildenafil is an inhibitor of phosphodiesterase activity however, the link between this function and CFTR trafficking correction remains to be elucidated. 

Whereas the suspected mechanism for ischemic stroke is analogous to that leading to myocardial infarction (hypoperfusion distal to a critical lesion), intracerebral bleeding (14,15) may be more difficult to explain. The authors considered the likelihood of sildenafil-induced spontaneous intracerebral hemorrhage due to the vasodilatory effects of the drug on the cerebral vasculature (as evidenced by headache, flushing, and nasal congestion). 

Gratz SR, Gamble BM, Flurer RA. Accurate mass measurement using Fourier transform ion cyclotron resonance mass spectrometry for structure elucidation of designer drug analogs of tadalafil, vardenafil and sildenafil in herbal and pharmaceutical matrices. Rapid Commun Mass Spectrom 2006 20 2317-2327. 

FF Chen, X.Y. Xie and Y.P. Shi, Magnetic molecularly imprinted polymer for the selective extraction of sildenafil, vardenafil and their analogs from herbal medicines, Talanta, 115 (482-489, 2013. 

---