代表讲稿2-Doripenem-ANewBroa.ppt

1、Doripenem - A New Broad-Spectrum Carbapenem Antibiotic,Group Member 0440213 0440216 0441515 0441523,SAR of doripenem,From Penicillins To Carbapenems,从青霉素到碳青霉烯 沙纳霉素（硫霉素，Thienamycin）的发现,Carbapenem before Doripenem,Structure of Doripenem,(1R,5S,6S)-2-(3S,5S)-5-substituted pyrrolidin-3-ylthio-6-(1R)-1-h

2、ydroxyethyl-1- methylcarbapen-2-em-3-carboxylic acids,Analysis of SAR,Mechanism Stability b-lactamase stability stability against human renal dehydropeptidase I (DHPI) Antimicrobial features Toxic effects,Mechanism,Like all beta-lactam antimicrobial agents, carbapenems act by inhibiting bacterial ce

3、ll wall synthesis by binding to and inactivating penicillin-binding proteins (PBPs).,b-lactamase stability,doripenem has a trans-configured 6-hydroxyethyl group, which protects it against beta-lactamases. Resistance to carbapenems develops when bacteria acquire or develop structural changes within t

4、heir PBPs, when they acquire metallo-beta-lactamases that are capable of rapidly degrading carbapenems, or when changes in membrane permeability arise as a result of loss of specific outer membrane porins. B-内酰胺环与二氢吡咯环反式拼合对B-内酰胺酶高度稳定。顺式则易被酶水解。 6-位引入立体因素较大的反式a-羟乙基侧链，降低了钝化酶对结构的适应性，保护B-内酰胺环不被B-内酰胺酶进攻。,

5、Human renal dehydropeptidase1(DHP1) stability,1-beta-methyl side chain provides resistance to the renal enzyme DHP1.,Antimicrobial Features,I.由于B-内酰胺环的张力较大，其中羰基氮原子上的孤对电子不能完全共轭，易受亲核进攻，且1位用亚甲基取代了硫原子，亚甲基sp3杂化的键角小于硫醚的键角，并由于C2与C3间双键的存在，使二氢吡咯趋于平面结构，活化了B-内酰胺环的反应活性，这是碳青霉烯类抗生素抗菌活性强的的化学基础 II.2位具有碱性烷基硫醚基团，使其更易

6、进入G-杆菌的细胞外膜。 III. C-3羧基使碱性下降，且是亲水基团可扩大抗菌谱，提高对G-的抑制作用和与蛋白的亲和力。,A particular feature, the side chain at position 2 sulfamoylaminomethyl group.,Toxic Effects,Doripenem displays favorable pharmacokinetic, pharmacodynamic and toxicological features, similar to those of meropenem. Doripenem has no convuls

7、ive activity. Doripenem did not cause any inhibition muscimol binding to the GABA receptor. So, its neurotoxicity may be negligible in clinical use.,Synthesis of doripenem,(1R,5S,6S)-6-(1R)-1-羟乙基-2-(3S,5S)-5-氨磺酰胺基甲基吡咯烷-3-基巯基-1-甲基-1-碳代-2-青霉烯-3-羧酸,(+)-(4R,5S,6S)-6-(1R)-1-hydroxyethyl-4-methyl-7-oxo-3(

8、3S,5S)-5-(sulfamoylaminomethyl)pyrrolidin-3-ylthio-1-azabicyclo 3.2.0 hept-2-ene-2-carboxylic acid monohydrate,Doripenem was synthesized by the condensation of (2S,4S)-1-t-butoxycarbonyl- 2-(N-t-butoxycarbonyl-sulfamoylamido) methyl-4-mercaptopyrrolidone (7) and (1R,5S,6S)-6- (1R)-1-hydroxyethyl-2-d

9、iphenoxyphosp hony loxy-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzylester (8), followed by deprotection with a yield of 50.5%. Compound 7 was obtained from trans-4-hydroxy-L-proline by esterification, protection, reduction, SN2 substitution, Mitsunobu reaction and alcoholysis with a yiel

10、d of 50.8%. The overall yield was about 26% (based on trans-4-hydroxy-L-proline). 反式-4-羟基-L-脯氨酸经酯化、保护、还原、SN2取代、 Mitsunobu反应、醇解得到（2S,4S)-1-叔丁氧羰基氨磺酰胺基）甲基-4-巯基吡咯烷（7），收率50.8%。7与（1R,5S,6S)-6-(1R)-1-羟乙基-2-二苯氧磷酰氧基-1-甲基-1-碳代-2-青霉烯-3-羧酸对硝基苄酯（8）缩合、脱保护，得到多尼培南，收率50.5%（以7计）。总收率接近26%（以反式-4-羟基-L-脯氨酸计）。,Step 1 Step

11、 2 Step 3 Step 4 Step 5 Step 6 NEXT,Step 1,-Boc: 叔丁氧羰基,保护氨基 -Ms:甲磺酰基,活化羟基,Step 2,酯基还原,还原剂的选择 SN2反应,4位发生构型反转,Step 3,Boc-NHSO2NH2: N-叔丁氧羰基氨磺酰胺 Mitsunobu Reaction 醇解脱去乙酰基,Step 4,化合物8:(1R,5S,6S)-6-(1R)-1-羟乙基-2-二苯氧磷酰氧基-1-甲基-1-碳代-2-青霉烯-3-羧酸对硝基苄酯(MAP,市售) 缩合反应,Step 5,脱掉-Boc保护基,Step 6,脱掉-PNB(对硝基苄基) 氢解反应,Mits

12、unobu Reaction,Research is a difficult job for us to challenge. Fighting!,Comparison of doripenem and other carbapenems,Comparison of doripenem and other carbapenems on pharmacology,Antibacterial mechanisms are the same with other beta-lactam antibiotics : combining with bacterial penicillin-binding

13、 protein (PBPs) inhibites bacterial cell wall synthesis. Doripenem has strong antibacterial activity and stability against the vast majority of beta-lactamase and kidney dehydrogenation endopeptidase (DHP) -1.,1. Antibacterial activity against G+,Methicillin- susceptible staphylococcus aureus, Staph

14、ylococcus epidermidis :slightly lower than imipenem, stronger than meropenem and biapenem Methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis :2 4 times stronger than other control drugs Strongest antibacterial activity to Streptococcus pyogenes,Penicillin- susceptible Streptococ

15、cus pneumoniae: similar to imipenem ,stronger than meropenem and biapenem Penicillin-resistant Streptococcus pneumoniae: identical with others Enterococcus faecalis: slightly lower than imipenem, strong in contrast to other drugs,Comparison of the MIC90(g/ml) for doripenem and three other carbapenem

16、s tested against Gram-positive pathogens,Strains (NO.) Doripenem Imipenem Meropenem Biapenem,Methicillin- susceptible staphylococcus aureus(30),0.063 0.032 0.125 0.125,Methicillin-resistant Staphylococcus aureus(30),16 32 32 64,Methicillin- susceptible Staphylococcus epidermidis(46),0.063 0.016 0.12

17、5 0.125,Methicillin- resistant Staphylococcus epidermidis(27),32 128 64 128,Streptococcus pyogenes(42),0.004 0.008 0.008 0.008,Penicillin- susceptible Streptococcus pneumoniae(25),0.008 0.008 0.016 0.016,Penicillin-resistant Streptococcus pneumoniae(25),0.5 0.25 0.5 0.5,Enterococcus faecalis(26),4 1

18、 8 8,MIC90 : MIC at which 90% of the strains were inhibited,2. Antibacterial activity against G-,Doripenem is sensitive to many G- bacteria, such as: E. coli Klebsiella pneumoniae (肺炎克雷白杆菌） Enterobacteriaceae （肠杆菌） Proteus mirabilis （奇异变形杆菌） Proteus vulgaris （普通变形杆菌） Haemophilus influenza （流感嗜血杆菌） P

19、. aeruginosa （铜绿假单胞菌）,Comparison of the MIC90(g/ml) for doripenem and three other carbapenems tested against Gram-negative pathogens,Strains (NO.) Doripenem Imipenem Meropenem Biapenem,E. Coli (30) 0.032 0.125 0.016 0.063 Klebsiella pneumoniae(30) 0.063 0.25 0.032 0.125 Aerobacter cloacae(30) 0.063

20、0.5 0.063 0.125 P. aeruginosa (83) 2 8 2 4 Proteus mirabilis(27) 0.5 4 0.125 2 Proteus vulgaris(30) 0.5 4 0.125 4 Haemophilus influenza(50) 0.5 4 0.25 4 MIC90 : MIC at which 90% of the strains were inhibited,3. Antibacterial activity against P. aeruginosa,Pseudomonas, a Gram-negative bacterium, is o

21、ne of the leading causes of resistant hospital-acquired infections and, because of increasing multi-drug resistance, treatment options are limited. Doripenem appears to have more potent in vitro activity against P. aeruginosa than meropenem.,Presence of carbapenem-resistant mutants withinzones of gr

22、owth inhibition of P. aeruginosa around cup,Doripenem could prevent growth of the mutants of P. aeruginosa at a concentration that would inhibit cell growth.,4. Pharmacokinetics,parenteral injection antibiotics the main metabolites :the beta-lactam ring hydrolysis untied product the product mainly b

23、y glomerulus filtration 90% of urine excretion,Conclusion,Doripenem is a promising new carbapenem with similar anti-G+ activity to those of imipenem and anti-G- activity to those of meropenem Doripenem had slightly greater activity against Pseudomonas aeruginosa.,Market prospects,Market prospects,Id

24、eal antibiotics: safe, efficient, broad-spectrum,The situation for antibiotics is:as they used in the large clinical application, resistant of bacteria has become increasing serious.,Market prospects,Overcome bacterial resistance from three aspects :,1. prevent the abuse of antibiotics .,2 .develop

25、new antibiotics .,3. Search the inhibitors of bacterial enzyme for hydrolysis of antibiotics.,Market prospects,Doripenem was first launched in Japan in Sep.2005. Its commercial name is Finibax. The injection had been licensed for the treatment of complicated intra-abdominal and complicated urinary t

26、ract infections. The nosocomial pneumonia indication for doripenem had been granted fast-track status by the FDA in Dec 2006.,Developing Process,Shionogi & Co., Ltd. (Osaka, Japan),“Finibax 0.25g IV Solution” launched in Japan in 2005,licensed to Peninsula Pharmaceuticals Inc. (Alameda, CA, USA),a s

27、ubsidiary of Johnson & Johnson, in 2005,Doripenem has received fast-track designation from the U.S. FDA for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia,In phase III trials for treatment of complicated intra-abdominal infection and complicated lower urinary tract

28、infections in 2006.12,Market prospects,In clinical trials, doripenem was well-tolerated. The most adverse events seen were diarrhea, nausea, constipation, urinary tract infection and decubitus ulcer, commonly known as a bedsore.,Market prospects,The current global situation of anti-infective market:

29、,anti-infective drug market sales account for about 15% of total sales, that is, the second of the global pharmaceutical market . Among them, antibiotics make the largest share, about 8 billion dollars. The carbapenem antibiotics is 1 billion annually.,Now carbapenem in the drug market share is risi

30、ng, the demand for carbapenem in market had increased by 50% last year. Thus carbapenem drug has been the hot development of antibiotics .,Market prospects,However, the potential exists for some metallo-b lactamases that can destroy carbapenem compounds to be more disseminated. prudent prescibing pr

31、actice should screen multidrug-resistant isolates for this mechanism. Only with this effort will doripenem be able to maintain its wide spectrum of activity and potential clinical utility.,Market prospects,References,4. Shihomi Sakyo, Haruyoshi Tomita, Koichi Tanimoto, Shuhei Fujimoto, Yasuyoshi Ike

32、. Potency of Carbapenems for the Prevention of Carbapenem-Resistant Mutants of Pseudomonas aeruginosa. J. Antibiot. 59(4): 220228, 2006,5. Masahito Horiuchi, Megumi Kimura, Miwa Tokumura,Nobuyoshi Hasebe, Tohko Arai, Kohji Abe Absence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with _-lactam antibiotics,1Ronald N. Jones,1,2* Holly K. Huynh,1 and Douglas J. Biedenbach1 Activities of Doripenem (S-4661) against Drug-Resistant Clinical Pathogens2 Shazad Mushtaq,1 Yigong Ge,2 and David M. Livermore1 Co