1. Phosphodiesterase(PDE) 5 inhibitor 1. Slidenafil (Viagra) 2. Tadalafil (Cialis) 2012. 07. 20 Lee, Sang-Hwi Ref. BMCL 1996, 6, 1819 BMCL 2003, 13, 1425

2. -2- 분포억제 시 부작용 PDE1 혈관, 심장, 뇌두통, 혈압 감소 PDE5 음경 내피세포 PDE6 망막색맹 ( 청색증 ) PDE11 골격근, 심장, 혈관근, 고환요통, 근육통, 정자 형성 감소증

3.  PDE5 is the major PDE isozyme in penile corpus cavernosum tissue and plays a key role in the control of penile erection.  Cyclic guanosine monophosphate (cGMP) is the ubiquitous second messenger for those G protein coupled receptors (GPCRs) 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 5 inhibitor.  There are at least seven families of PDE, of which three (types 1, 5 and 6) selectively hydrolyse cGMP relative to cAMP.  PDE type 5, the calcium/calmodulin insensitive cGMP phosphodiesterase, occurs in lung, platelets and various forms of smooth muscle. -3-

4.  Type 5 cGMP PDE is also the predominant cGMP hydrolysing activity in the cytosolic fraction from haman corpus cavernosum.  As penile erection is mediated by NO, and thus cGMP, inhibitors of type 5 PDE improve erection by enhancing relaxation of the corpus cavernosal smooth muscle, and thereby have utility for the treatment of male erectile dysfunction (impotence).  We here report the discovery of sildenafil (VIAGRA TM), a potent and highly selective inhibitor for the type 5 PDE, that is an orally active treatment for male erectile dysfunction. -4-

5. Vascular smooth muscle -5- actin-myosin cross bridging Contraction ( 수축 ) NO Relaxation ( 이완 ) GTP cGMP Guanylyl cyclase SR : 근육세포질세망

6. Mechanism of action -6-

7. -7- 작용개시 시간까지 더 긴 시간 필요 T 1/2 길다

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10. Sildenafil and vardenafil show excellent PDE 5 selectivity over PDE 11 (760- and 1160-fold, respectively) whereas tadalafil exhibits only a modest 5-fold selectivity. It has been suggested that PDE 11 protein localization in man and mouse, coupled with the known role for cGMP and cAMP in sperm physiology and testosterone production, suggests a local role for PDE 11 in testis development and/or spermatogenesis. The presence in acidophils also suggests a role in modulating secretion of prolactin and/or growth hormone, hence an indirect/ endocrine effect on lactation, luteal function, steroidogenesis, immunoregulation and growth, for example, as well as on the testis and spermatogenesis. The physiological significance of PDE11 inhibition is not clearly understood but could have a role in sperm function. Thus, in the future PDE11 inhibitors might be explored for novel indications relating to hormonal or other functions, but when developing PDE5 inhibitors to modulate vascular function it was thought desirable to maintain high selectivity of PDE5 effects over PDE11. -10-

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