Erectile dysfunction Sildenafil Tadalafil 2015 5 8 FRI

Erectile dysfunction ▶ Sildenafil ▶ Tadalafil 김연수 2015. 5. 8. FRI

Sildenafil란? 발기부전 치료제(Viagra) 화학명 분류 1 -[4 -ethoxy-3 -(6, 7 -dihydro-1 -methyl 7 -oxo-3 -propyl-1 H-pyrazolo[4, 3 -d]pyrimidin-5 -yl) phenylsulfonyl]-4 -methylpiperazine 비내분비성 발기부전 치료제, 혈관 확장제 Phosphodiesterase 5 -inhibitor(PDE 5 -inhibitor) 약리 주성분(API) Sildenafil Citrate 혈관 평활근을 이완시키고 음경 해면체에 혈류를 충만 케함 Sildenafil Citrate 약효를 발현하는 주요 부분 Sildenafil을 제제화 하는데 있어 안정성을 돕게 해주는 Salt

Tadalafil란? 발기부전 치료제(Cialis) 화학명 (6 R-trans)-6 -(1, 3 -benzodioxol-5 -yl)-2, 3, 6, 7, 12 ahexahydro-2 -methyl-pyraino[1’, 2’: 1, 6]pyrido[3, 4 b]indole-1, 4 -dione 분류 비내분비성 발기부전 치료제, 혈관 확장제 약리 Phosphodiesterase 5 -inhibitor(PDE 5 -inhibitor) 장점 다른 약에 비해 지속시간이 길다

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작용원리 www. youtube. com/watch? v=PCD 02 Mt. ZIz. U

Design, Synthesis and Biological Activity of β-Carboline-Based Type-5 Phosphodiesterase Inhibitors Graham N. Maw, * Charlotte M. N. Allerton, Eugene Gbekor and William A. Million Bioorganic & Medicinal Chemistry Letter 13 (2003) 1425– 1428

Abstract • The SAR of a series of β-Carboline derived type 5 phosphodiesterase inhibitors has been explored and we have discovered compounds with excellent levels of PDE 5 potency and selectivity over PDE 6. • However, the series exhibits low levels of selectivity over PDE 11, a phosphodiesterase with unknown function.

Introduction • Secondary messenger cyclic nucleotides - Adenosine cyclic 3’, 5’-phosphate(c. AMP) - Cyclic guanasine 5’-phospate(c. GMP) c. GMP specific PDE 5 enzyme controls the levels of intracellular c. GMP and plays a critical role in its modulation, duration of action and physiological function. - PDE 5 is the major PDE isozyme in penile corpus cavernosum tissue and plays a key role in the control of penile erection.

Introduction - During sexual stimulation nitric oxide(NO) is released - Activates guanylate cyclase to form c. GMP via cyclisation of GTP. - Resulting in stimulation of c. GMP synthesis, which, in turn, reduces intracellular calcium following binding to c. GMP-dependant protein kinases and c. GMP-dependant ion channals.

Introduction - Sildenafil & Vardenafil, show excellent PDE 5 selectivity over PDE 11. Whereas Tadalafil exhibits low selectivity. - PDE 11 inhibition is not clearly understood but could have a role in sperm function. - In the future, PDE 11 inhibitors might be explored for novel indications relating to hormonal or other functions, but when developing PDE 5 inhibitors to modulate vascular function it was thought desirable to maintain high selectivity of PDE 5 effects over PDE 11.

Scheme 1

Table I Flexible linker Pyrrolidine 12 showed an 8 fold increase in enzyme inhibition potency

Scheme 2

Table Ⅱ

Table Ⅲ This series of compounds was also found to be non selective over PDE 11

Summary - Extensive SAR exploration of the β-carboline template has identified a range of compounds exhibiting excellent PDE 5 potency and selectivity over PDE 6. - However, these compounds are not selective for PDE 5 over PDE 11.

Synthesis and Pharmacological Evaluation of Sildenafil Analogues for Treatment of Erectile Dysfunction Haroldo A. Flores Toque, Fernanda B. M. Priviero, Cleber E. Teixeira, Elisa Perissutti, Ferdinando Fiorino, Beatrice Severino, Francesco Frecentese, Raquel Lorenzetti, Juliana S. Baracat, Vincenzo Santagada, Giuseppe Caliendo, Edson Antunes, and Gilberto De Nucci J. Med. Chem. 2008, 51, 2807 -2815

Introduction - The main therapeutic indications for PDE 5 inhibitors are the treatment of erectile dysfunction and idiopathic pulmonary hypertension - Common side-effects include headache, facial flushing, nasal congestion, dyspepsia, and transient visual impairment

Table Ⅰ

Scheme 1

Table Ⅱ

Table Ⅲ Because these compounds are more lipophilic than sildenafil, they may have better bioavailability and prolonged action in vivo.

Scheme 2