Phosphodiesterase Inhibitor Chapter 15 PDE 관련 약물 Phosphodiesterase Inhibitor

Summary of PDEs PDE degrade the phosphodiester bond in cAMP & cGMP PDE4, 7 and 8: cAMP selective hydrolases PDE5, 6 and 9: cGMP selective hydrolases PDE1, 2, 3, 10 and 11: hydrolyse both cAMP and cGMP Inhibitors of PDE can prolong or enhance the effects of physiological processes mediated by cAMP or cGMP by inhibition of their degradation by PDE. PDE inhibitors in clinical use PDE 3 inhibitor: Inamrinone (울혈성심부전증 치료제) PDE 4 inhibitor: Roflumilast (천식, 만성기관지염 치료제) PDE 5 inhibitor: Sildenafil, Vardenafil (발기부전 치료제)

The PDE for c-AMP and c-GMP For c-GMP

Binding Mode for Adenine and Guanine

The mechanism of PDE Coordination of M+ with O Nucleophilic addition Protonation

Classification of PDE

The PDEs and Biological Role

The function of PDE-3 Inh. 혈관확장, 혈소판 응집 억제 : 혈류 흐름 증가-심근경색 예방, 혈전 방지 : dipyridamole, Clisostizol Inamrinone(amrinone): 혈관확장, 심장수축증대- 울혈성 심부전 치료

The function of PDE-4 Inh. Roflumilast: 만성폐기종,호흡기 염증치료 Cilomilast: Asthma :기관지 천식

PDE – 4 Inhibitors Clinical Application of PDE4 inhibitors A phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system Clinical Application of PDE4 inhibitors Chronic obstructive pulmonar disease (COPD) Bronchopulmonary dysplasia (BPD) Asthma Depression Alzheimer's, Parkinson's

The function of PDE-4 Inh

The Function of PDE-4 Inh.

The Function of PDE-5 Inh. Increasing c-GMP conc.-Smooth muscle relaxation-increasing blood flow -erection

The Mechanism of Erection

Introduction of Viagra

The PDE 5-Inhibitors

Clniical application of PDE-5 Erectile dysfunction Drugs that inhibit PDE5, sildenafil, tadalafil and vardenafil, have been used as treatment for erectile dysfunction.[13] These inhibitors increase the cGMP, smooth muscle relaxation and consequentally cause penis erection[6] during sexual stimulation.[14 Pulmonary hypertension Pulmonary hypertension is the result of upregulation of PDE5 gene expression, causing vasoconstriction in the lung. PDE5 inhibitors are used as potent pulmonary vasodilators reducing Pulmonary hypertension[4] and inhibiting vascular remodelling.[15] Long-term treatment with a PDE5 inhibitor has been shown to enhance natriuretic peptide-cGMP pathway, downregulate Ca2+ signaling pathway and alter vascular tone in pulmonary arteries in rat models

Future indications for PDE5 inhibitors Premature ejaculation Adding PDE5 inhibitors to SSRI drugs (e.g. paroxetine) for the treatment of premature ejaculation could result in better ejaculatory control according to recent studies.[8] Possible mechanism is based on nitric oxide (NO)/cGMP transduction system as a central and peripheral mediator of inhibitory non-adrenergic, non-cholinergic nitrergic neurotransmission in the urogenital system.[ Female sexual arousal disorder PDE5 is expressed in clitoral corpus cavernosum and in vaginal smooth muscle and epithelium. Therefore it is possible that PDE5 inhibitors could affect female sexual arousal disorder but further research is needed. Increased levels of cGMP have been shown to occur in human-cultered vaginal smooth muscle cells treated with a PDE5 inhibitor suggesting involvement of the NO/cGMP axis in the female sexual response.[8] Heart failure Sildenafil has shown promise in the treatment of congestive cardiac failure. A study showed that effective treatment of pulmonary arterial hypertension with sildenafil improved functional capacity and reduced right ventricular mass in patients. The effects on right ventricular remodeling were significantly greater in comparison with the non-selective endothelia receptor antagonist bosentan. Cardiovascular disease and systemic hypertension Sildenafil has been shown to improve endothelial function in diabetes and congestive heart failure.,[4][16] It has also been shown to reduce aortic pressure through vasodilation, reduced arterial stiffness and wave reflection and could be used in the management of systemic hypertension.[4]

How do you think about it? Another hypertensive agent

신약 개발기업 동아팜텍 (대표 박동현)은 23일 현재 발기부전치료제로 판매 중인 자이데나 (성분명: 유데나필)가 미국 현지서 전립선비대증 치료제로 용도특허를 획득하였다고 밝혔다. 용도특허는 신약물질이 가진 특허권리 중 하나로 향후 특허가 만료되기 전 기존의 다른 제약회사가 같은 용도(전립선비대증)의 제품을 시장에 출시하지 못한다는 것을 의미한다. 회사측은 "캐나다와 함께 북미지역서 두번째로 전립선비대증 치료제 용도특허를 획득함으로써 북미시장에서 적응증 확대를 위한 임상계획을 순차적으로 진행할 수 있게 됐다"고 말했다. 전립선비대증치료제 전세계 시장은 60억 달러 규모로 현재 알파블로커 (alpha-blocker)가 주된 치료제로 사용되고 있는 거대시장이다. 현재 자이데나와 같은 계열 (PDE5 inhibitor)인 시알리스가 2011년 말 전립선비대증 치료제로 미국 FDA로 부터 최종승인 받은바 있다. 동아팜텍은 이미 미국 FDA와 pre-IND meeting을 통하여 자이데나에 대한 전립선비대증치료제로 임상 시험 허가(Phase 2b)를 받아놓은 상태이며, 북미지역 계약 파트너사인 워너칠코트 (Warner Chilcott)가 북미에서 개발을 진행할 예정이다 한국릴리는 매일 복용하는 발기부전 치료제 시알리스 5mg(성분명 타다라필)의 적응증이 전립선 비대증으로 확대됐다고 25일 밝혔다. 한국릴리에 따르면 식품의약품안전청은 최근 시알리스 5mg에 대해 기존 발기부전 치료에 대한 적응증 외에 '양성 전립선 비대증의 징후 및 증상 치료', '발기부전 및 양성 전립선 비대증 징후 및 증상 동반 치료'에 대한 적응증을 추가로 승인했다. 식약청은 1989명의 남성을 대상으로 시알리스의 효과 및 안전성을 입증한 세 건의 임상연구 결과에 근거해 시알리스의 이번 적응증을 추가로 승인했다. 한국릴리 관계자는 "시알리스는 이번 적응증 추가를 통해 중년 이상 남성들에게 가장 흔한 발기부전과 양성 전립선 비대증을 동시에 치료하는 방법을 제공하게 됐다"고 말했다.

The Mechanism of Erection and Prostatic muscle

Summary of PDEs PDE3 Inh. -Milrinone -Enoximone -Amrinone - Cilostazol -Roipram -Roflumilast -Cilomilast PDE5 Inh. -Sildenafil -Vardenafil -Tadalafil

Natural Viagra The amino-acid citrulline was first extracted from watermelon and analyzed.Watermelons contain a significant amount of citrulline and after consumption of several kilograms, an elevated concentration is measured in the blood plasma In recent studies, citrulline has been found to relax blood vessels. Circulating citrulline concentration is, in humans, a biomarker of intestinal functionality

Arginine and Nitic Oxide NOS

수박 + 석류 = 천연 비아그라 ???

Sildenafil 1-[4-ethoxy-3-(6,7-dihydro-1-methyl- 7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl) phenylsulfonyl]-4-methylpiperazine Viagra®(Pfizer), 비아그라 정(한국화이자) PDE 5 inhibitor: 발기부전치료제

Binding mode of sildenafil

Retrosynthesis Sildenafil nitration

Synthesis Sildenafil

Vardenafil 4-[2-Ethoxy-5-(4-ethylpiperazin-1-yl)sulfonyl-phenyl]- 9-methyl-7-propyl-3,5,6,8-tetrazabicyclo[4.3.0]nona- 3,7,9-trien-2-one Levitra®(Bayer), 레비트라 정(바이엘), 야일라 정(종근당) PDE 5 inhibitor: 발기부전치료제

Binding of Vardenafil

Retrosynthesis Vardenafil

Synthesis Vardenafil

Synthesis Vardenafil

Dakin-West Reaction Vardenafil

Modified Dakin-West Reaction

Triazone synthesis

Tadalafil

Synthesis

Udenafil

Viagra, Levitra and Cialis pharmacokinetics Side effects

Viagra,Levitra, Cialis 복용방법

Inamrinone 5-Amino-3,4’-bipyridine-6(1H)-one 3-Amino-5-(4-pyridinyl)-2(1H)-pyridinone Amrinone®(Bedford), 암리논 주(이연) PDE 3 inhibitor: 울혈성심부전증 치료제

Retrosynthesis Inamrinone

Synthesis Inamrinone

Dipyridamole 2,2',2'',2'''-(4,8-di(piperidin-1-yl)pyrimido[5,4-d] pyrimidine-2,6-diyl)bis(azanetriyl)tetraethanol 2,6-Bis(diethanolamino)-4,8-dipiperidinopyrimido [5,4-d]pyrimidine Persantine®(Boeringer Ingelheim), 슈넬 펜톡시필린 주(슈넬) PDE inhibitor (cAMP) & thromboxane synthase inhibitor 항혈소판응고작용, 항기관지수축작용, 항혈관수축작용

Retrosynthesis 1

Synthesis 1

Retrosynthesis Dipyridamole

Synthesis Dipyridamole

Roflumilast 3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)- 4-(difluoromethoxy)benzamide Dalilresp®(Forrest Pharmaceuticals), 국내 유통품목 없음 PDE 4 inhibitor: 만성기관지염, 천식, 만성폐쇄성폐질환 치료제 (chronic obstructive pulmonary disease, COPD)

Retrosynthesis Roflumilast Ether bonding amidation

Synthesis Roflumilast