School of Pharmacy, Sungkyunkwan University

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1 School of Pharmacy, Sungkyunkwan University
itraconazole Sook-Jin Park School of Pharmacy, Sungkyunkwan University FRI. SEMINAR

2 담자균류(Basidiomycetes) 불완전균류(Fungi imperfecti)
Itraconazole 항진균제란? - 진균의 생장, 생식 등을 억제하는 작용이 있 는 물질의 총칭 진균의 특징 - 진핵생물로 염색하지 않아도 관찰이 가능. 대 부분 호기성, 20~30도에서 잘 자란다 진균의 분류 접합균류(Zygomycetes) 자낭균류(Ascomycetes) 담자균류(Basidiomycetes) 불완전균류(Fungi imperfecti) 효모(Yeast)

3 Itraconazole 화학명 분류 항진균제(imidazole 계열) 약리
Levofloxacin 화학명 (2R,4S)-rel-1-(butan-2-yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-ichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-4,5-dihydro-1H-1,2,4-triazol-5-one 분류 항진균제(imidazole 계열) 약리 곰팡이 세포막의 ergosterol의 합성을 저해시킴 적응증 무좀, 조갑 진균증, 칸디다성 질염, 체부백선, 고부백선, 수부백선, 족부백선 상품명 Sporanox 개발회사 Janssen

4 작용기전에 따른 항진균제의 분류 계열 종류 기전 Polyene계 Amphotericin B
진균 세포막의 ergosterol에 직접 결합해서 세포막의 투과성을 증가시켜 세포 내 구성성분을 유출시켜 세포를 죽인다 Nystatin Candicidin Azole계 - Imidazole miconazole 진균의 cytochrome P-450 효소중 하나와 결합해서 ergosterol의 생합성을 방해한다 장점 : 1)넓고 우수한 항진균제 2)적은 부작용 3)투약의 간편성 itraconazole Azole계 - Triazole Ketoconazole fluconazole voriconazole Allylamine Naftifine Squalene epoxidase를 억제해서 ergosterol 생합성을 방해함 Squalene →squalene-2,3 oxide →lanosterol→ergosterol 특징 : 피부사상균에만 효과적 terbinafine Thiocarbamate tolnaftate

5 작용기전에 따른 항진균제의 분류 계열 종류 기전 Ergosterol 생합성을 억제함 억제 효소가 독특하다
기타 Amorolfine (로세릴 크림) Ergosterol 생합성을 억제함 억제 효소가 독특하다 Sterol – 14-reductase Sterol – 7,8 isomerase Cicloppirox olamine (로푸록스) 진균의 세포막에 작용, 세포막 생합성에 필요한 필수물질과 전해질의 이동을 방해한다 Flucytosine (안코본 캅셀) 진균세포 내에서 5-FU, 5-fluororidylic acid로 변환된 후 RNA, DNA의 기능을 억제하여 항진균 효과를 나타냄 Griseofulvin (홀비신 정) 진균의 세포막 합성을 억제

6 Itraconazole Polyene계 Amphotericin B 특징
Streptomyces nodosus에서 분리한 항진균제로 전신용 진균 치료제로 처음 사용된 약물이다. 물에는 잘 녹지않아 경구투여 혹은 근육 주사시 흡수가 되지 않으며 현재 현탁액(i.v. infusion)으로 시판 됨 부작용 일반적으로 두통, 오심, 오한, 발열, 피로감, 설사, 부정맥, 피부발진 등을 보일 수 있으며 심한 경우 신독성을 유발하여 혈중요소의 증가로 산혈증을 보이기도 한다 Polyene계

7 Itraconazole Allylamine Terbinafine 특징
Allylamine유도체로서 Aspergillus spp. 와 Candida spp. 등에 유효한 것으로 알려져 있다. 부작용 Terbinafine은 간에서 대사를 많이 받으며 투여한 용량의 80%가 뇨로 배설되고 나머지는 변으로 배설되므로 간기능 부전이나 신기능 저하된 환자의 경우 AUC가 증가됨으로 주의를 요한다. Allylamine

8 Itraconazole Azole계 - Triazole Ketoconazole 특징
1979년에 개발된 최초의 경구용 항진균제로 조직분포가 크고 생물학적 반감기가 긴 이유로 많이 사용되었으나 현재는 그 부작용으로 다른 약물로 대체되고 있다. 부작용 용량 의존성으로 구토 등의 부작용이 있다. 항남성 호르몬 효과가 있어 여성형 유방 및 성욕 감퇴가 나타날 수 있다. 투여환자의 2~8%에서 혈청 transaminase의 일시적 상승이 나타났으나 투여 중단 후 가역적으로 정상치를 회복함 Azole계 - Triazole

9 Itraconazole Azole계 - Triazole Fluconazole 특징
물에 잘 녹는 fluorine이 치환된 bis-triazole계 항진균제로 면역기능이 저하된 환자의 전신성 진균감염증에 유효한 것으로 알려져 있다. 부작용 내약성이 좋은 편으로 부작용의 발현은 드문편이나 구역, 설사, 복부팽만, 두통, 어지러움 등이 올 수 있다. Azole계 - Triazole

10 Itraconazole(Sporanox)
특징 지용성이 크며 ketoconazole에 비하여 항균범위가 크고 병원성 진균에 대하여 우수한 효능을 나타내고 독성도 더 적다 부작용 Itraconazole의 모든 부작용은 일시적이며 위장장애, 두통, 성욕감퇴, 백혈구 감소 등이 나타날 수 있다. 간독성은 낮은 편이며 3%이하의 환자에서 일시적인 간 효소치의 상승이 나타난다. Ketoconazole과 같은 항남성 호르몬의 부작용은 나타나지 않는다. Azole계 - Imidazole

11

12 Antimycotic Azoles. 6. Synthesis and Antifungal Properties of Terconazole,
a Novel Triazole Ketal J.Med.Chem. 1983, 26, 항진균제(imidazole 계열)

13 Introduction Miconazole ( 1), clotrimazole (2), and ketoconazole (3a) are widely used for the treatment of fungal diseases. Unlike miconazole and clotrimazole, ketoconazole is well absorbed in the bloodstream. ketoconazole has been found to be highly effective against crop candidosis in turkeys, vaginal candidosis in rats, systemic candidosis in chickens, systemic and skin candidosis, as well as dermatophytosis, in guinea pigs, and coccidioidomycosis in mice.

14 Introduction As a result of our continuous search for new antifungal
agents, in particular azole ketals We report the synthesis and antifungal properties of terconazole (3b), a novel triazole ketal.

15 Biological Result In vitro
At this concentration, terconazole is devoid of activity against Escherichia coli.

16 Biological Result In vivo
In experimental vaginal candidosis, 0.5% terconazole b.i.d. for 3 days is equivalent or superior to 1 % clotrimazole.

17 Conclusions After oral administration, terconazole is less active than ketoconazole in vaginal candidosis Based on available biological results, it can be expected that terconazole will be effective in topical treatment of superficial fungal infections of different etiology Terconazole has a high topical in vivo activity against vaginal candidosis in rats and against dermatophytosis in guinea pigs

18 Antimycotic Azoles. 7. Synthesis and Antifungal Properties of a Series of Novel Triazol-3-ones
J.Med.Chem. 1984, 27, 항진균제(imidazole 계열)

19 Introduction With the advent of ketoconazole (Ia), which was discovered approximately 30 years after the development of the first orally active broad-spectrum antibiotics, the first oral broad-spectrum antimycotic became available for medical practice. The in vitro spectrum of ketoconazole covers a wide variety of yeasts, dermatophytes, and other fungi

20 Results and Discussion
Compound 68, when tested in MezSO solution in Sabouraud broth at pH 7.4, was active against dermatophytes at concentrations ranging from 0.1 to 1 pg/mL and against Candida spp., Cr. neoformans, A. fumigatus, S. schenckii, and Ph. verrucosa at 0.1 Mg/mL.

21 Results and Discussion
compounds (39,53,58, and 67) appear to be active at rather low concentrations (1-10pg/mL) against dermatophytes, such as T. rubrum, T.mentagrophytes, and yeasts, such as Cr. neoformans and C. tropicalis

22 Results and Discussion
It is striking that even at 100 pg/mL none of the tested compounds showed significant activity against Mucor sp., and only one compound (40) showed significant activity against M. canis.

23 Results and Discussion
Compound 67 was active against T. mentagrophytes, T.rubrum, Cr. neoformans, and C. tropicalis and was the only compound that had an inhibitory effect on the growth of S. schenckii at 100 pg/mL. By comparison, it can be concluded that in vitro and in vivo activity are very poorly correlated.

24 Results and Discussion
Although none of the triazol-3-ones displays any in vitro activity against M. canis at 100 pg/mL, when tested under the conditions described, several compounds (39, 47, 62 and 66-68) demonstrated significant oral activity against experimental microsporosis, even at low doses (2.5 mg/kg).

25 Results and Discussion
in vivo results prove that it is favorable to substitute a triazole ring for the imidazole moiety (46 < 62 and 53 < 68). Nonalkylated triazol-3-ones were less potent than the alkylated analogues.

26 Results and Discussion
Introduction of a methyl group in the 5-position of the triazol-3-one ring (R2) tends to decrease the oral activity, in particular in microsporosis (66 > 65 and 62 > 63, and 68 > 72).

27 Results and Discussion
Alkyl chain (R1)from methyl to n-propyl(56,58, and 60) in the trizaoles, whereas the n-butyl derivative(64) is devoid of activity. Replacement of the n-propyl(60) by an allyl chain(67) tends to decrease the activity against vaginal candidosis, but, on the other hand, an important increase in activity against microsporosis is noticed.

28 Results and Discussion
Branching of the alkyl chain gives rise to a dramatic increase of activity against vaginal candidosis, as well as against microsporosis(62,66 and 68). Introduction of a cyclopropylmethyl group(71) for isobutyl(66) leads to a decreased activity in both infection medels.

29 Conclusions Based on the results, also gained from other animal modeIs, one compound [68, (itraconazole, proposed international nonproprietary name)] has been selected for clinical studies.

30 Janssen 사 Synthesis

31

32 Itraconazole

33 Itraconazole

34 Itraconazole

35 Itraconazole

36 Itraconazole

37 Itraconazole

38 Itraconazole

39 Itraconazole

40 Itraconazole

41 Itraconazole

42 Itraconazole

43 Itraconazole