Adviser： Jya-Wei Cheng Speaker ： Li-Chun Chen ( )

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1 Adviser： Jya-Wei Cheng Speaker ： Li-Chun Chen (9780614)
Cimetidine Adviser： Jya-Wei Cheng Speaker ： Li-Chun Chen ( )

2 Disease

3 Gastric acid release X X X X Oesophagus :['safәgәs]食道 Antrum:【解】竇,腔,房
Pyloric sphincter:幽門括約肌 Duodenum:[ˏdjuә'dinәm] 十二指腸 Parietal:[pә'raıәt!] 【生】腔壁的 Gastric juice : digest enzymes + HCl Antrum含有G-cell(hormone-producing cell)，當食物存在時，會刺激胃泌素(Gastrin,polypeptide)的產生 在食物進到胃之前，所有的感覺包括:嗅覺、味覺、甚至是想像都會使Acetylcholine刺激自主神經活化cholinergic receptor 組織胺可以促進H2 receptor活化質子幫浦 →刺激質子幫浦釋放氫質子。 因為神經系統也有利用Cholinergic receptor接收Acetylcholine產生神經訊號的傳導，所以抑制Cholinergic receptor會使神經系統出現問題。 當胃裡面沒有食物，Antrum G-cell不會被刺激，所以Cck2 receptor不會刺激質子幫浦分泌氫質子，因此，阻斷Cck2的功能對胃潰瘍並沒有幫助。

4 Cimetidine The first breakthrough in antiulcer therapy came with the design of the H2 antagonist. The program started in 1964 Produced by company SmithKline and French(SKF) , now GlaxoSmithKline(GSK) Cimetidine的發展很特殊，其實1960年代的時候，還沒有發現H2 receptor，SKF公司僅僅只根據組織胺抑制胃酸產生的in vitro 實驗，決定開發抗組織胺的藥物，在當時是相當冒險的。這個計畫在不知道藥物目標target，也不知道lead compound的情況下開始。所以，在幾乎完全從零開始的開發過程中，它應該算是一個相當具代表性的藥物。 Sir James W. Black shared the 1988 Nobel Prize in Physiology or Medicine for the discovery of propranolol and also is credited for the discovery of this drug; actually, the medicinal chemists would have made the discovery)

5 Cimetidine Be approved by the Food & Drug Administration (FDA)for prescriptions starting January 1, 1979. Trade name： Tagamet、 Tagamet HB 、 Tagamet HB200 Cimetidine became the first drug ever to reach more than $1 billion a year in sales.

6 How to design ? Main theory：
The histamine receptor which is involved in the inflammation process is classified as H1 receptor . → H2 receptor (be responsible for gastric acid secretion). Lead compound： Started from histamine itself. 當時還沒發現H2 receptor，而且沒有現在所謂的lead compound，但是研究人員在in vitro實驗中，發現Histamine會影響胃酸的分泌，所以他們推測胃裡面應該有一個類似H1 receptor的受體。 Lead compound：Histamine

7 How to design ? Structure-activity studies (SAR)：
Side chain had to be positive charged nitrogen atom with at least one attached proton. Quaternary ammonium salts which lacked such a proton were extremely weak in activity. There had to be a flexible chain between the above cation and a heteroaromatic ring. The heteroaromatic ring did not have to be imidazole, but it did have to contain a nitrogen with a lone pair of electron, ortho to the side chain. 側鏈N上的正電荷 可轉動的側鏈及heteroaromatic ring heteroaromatic ring上的N必須帶有lp，且lp與側鏈以ortho形式存在

8 How to design ? Structure-activity studies (SAR)：
Aromatic ring with lone pair Flexible chain Positive charge on “N” H2 receptor - heteroaromatic ring - amidine unit (HN-CH-N:) H2 receptor - heteroaromatic ring amidine unit (HN-CH-N:) → 形成氫鍵

9 How to design ? Receptor binding interaction： two binding site
three binding site

10 4-methylhistamine Analogues variation
Not antagonist, but highly selective for H2 receptor Not an antagonist

11 4-methylhistamine Two conformation H2 receptor favor H1 receptor favor
1) High flexible H2 receptor favor H1 receptor favor

12 Nα-guanylhistamine Altered agonist to antagonist：
必須將原本促進功能轉變成抑制，所以必須改變 receptor與 ligand 原來的結合方式。 在Nα上作取代這個想法來自於一種腎上腺素抑制劑 isoprenaline。

13 Nα-guanylhistamine Modfication Nα-guanylhistamine 他是一個弱的antagonist
其實它還是會讓胃酸釋放，但因為它會使H2 receptor的構型改變，所以產生的胃酸比histamine少。 Nα-guanylhistamine

14 Nα-guanylhistamine Interaction between Nα-guanylhistamine & receptor

15 Chain length extension

16 Agonist to antagonist

17 Synthesis of Cimetidine

18 Metabolism of Cimetidine
Cimetidine itself is metabolically stable and is excreted largely unchanged. Inhibits the cytochrome P450 enzymes in liver. Caution is required when cimetidine is taken with diazepam, lidocaine, warfarin, or theophylline. Theophylline:茶鹼 warfarin:類抗凝血劑 Lidocaine:麻醉藥 diazepam:一種鎮靜安眠藥 1) 2) Cimetidine抑制肝臟cytochrome P450的作用，會造成其他藥物無法代謝，在血液中維持高濃度。 3)

19 Thanks for Your Attention！