Transcript Doripenem - A New Broad-Spectrum Carbapenem Antibiotic

Doripenem - A New BroadSpectrum 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-hydroxyethyl]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
cell 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 their 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。
Human renal dehydropeptidase1
(DHP1) stability
1-beta-methyl side chain
provides resistance to the
renal enzyme DHP1.
Antimicrobial Features
A particular feature, the side chain at
position 2 —sulfamoylaminomethyl
group.



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。
Toxic Effects
Doripenem displays favorable
pharmacokinetic, pharmacodynamic and
toxicological features, similar to those of
meropenem.
 Doripenem has no convulsive 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-7oxo-3[[(3S,5S)-5-(sulfamoylaminomethyl)pyrrolidin-3yl]thio]-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-butoxycarbonylsulfamoylamido) methyl-4-mercaptopyrrolidone (7) and
(1R,5S,6S)-6- [(1R)-1-hydroxyethyl]-2-diphenoxyphosp
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-4hydroxy-L-proline by esterification, protection, reduction,
SN2 substitution, Mitsunobu reaction and alcoholysis
with a yield 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）。
HO
HO
COOH
N
H
MsO
1. (Boc)2O
CH3OH , SOCl2
2
MsO
2. CH3SO2Cl
COOMe
N
HCl . H
Boc
AcS
3
CH3COSK
KBH4 / ZnCl2
OH
N
COOMe
N
OH
N
Boc
Boc
5
4
AcS
HS
Boc
(C6H5)3P
Boc
CH3ONa
Boc-NHSO2NH2
CH3OH
NSO2NH2
N
Boc
Boc
7
6
OH
H H
NSO2NH2
N
O
OP(OPh)2
N
CO2PNB 8
O
OH
H H
(i-Pr)2NEt
N
O
Boc
S
OMe
AlCl3/
NSO2NH2
CO2PNB N
Boc
9
OH
H H
N
O
OH
H H
Pd/C
S
CO2PNB N
H
NHSO2NH2
N
COOH
O
N
H
NHSO2NH2
1
10
Step 1
S
Step 2
Step 3
Step 4
Step 5
Step 6
NEXT
Step 1
HO
HO
1. (Boc)2O
CH3OH , SOCl2
N
H
COOH
N
HCl . H
COOMe
2
2. CH3SO2Cl
MsO
N
Boc
3
-Boc: 叔丁氧羰基,保护氨基
-Ms:甲磺酰基,活化羟基
COOMe
Step 2
MsO
MsO
AcS
CH3COSK
KBH4 / ZnCl2
N
COOMe
N
Boc
Boc
3
4
OH
酯基还原,还原剂的选择
SN2反应,4位发生构型反转
N
Boc
5
OH
Step 3
AcS
AcS
N
Boc
5
OH Boc-NHSO2NH2
HS
Boc
(C6H5)3P
Boc
CH3ONa
NSO2NH2
N
Boc
6
CH3OH
N
Boc
7
Boc-NHSO2NH2: N-叔丁氧羰基氨磺酰胺
Mitsunobu Reaction
醇解脱去乙酰基
NSO2NH2
Step 4
HS
Boc
N
Boc
7
NSO2NH2
OH
H H
N
O
O
OP(OPh)2
CO2PNB 8
OH
H H
(i-Pr)2NEt
N
O
Boc
S
CO2PNB N
NSO2NH2
Boc
9
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
OH
H H
N
O
Boc
S
CO2PNB
N
Boc
9
脱掉-Boc保护基
OMe
AlCl3/
OH
H H
NSO2NH2
N
O
S
CO2PNB N
H
10
NHSO2NH2
Step 6
OH
H H
N
O
Pd/C
S
CO2PNB N
H
OH
H H
NHSO2NH2
10
脱掉-PNB(对硝基苄基)
氢解反应
N
S
COOH
O
1
N
H
NHSO2NH2
Mitsunobu Reaction
O
EtO
O
O
N N
OEt
+
R'3P
EtO
O
OEt
N N
R'3P+
HX
O
EtO
O
N NH
OEt . X -
R2OH
O
R'3P+ OR2. X-
+ EtO
R'3P+
R'3P O
+
R2X-
O
N
H
N
H
OEt
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
protein (PBPs) inhibites bacterial cell wall
synthesis.

Doripenem has strong antibacterial activity and
stability against the vast majority of betalactamase and kidney dehydrogenation
endopeptidase (DHP) -1.
1. Antibacterial activity against G+

Methicillin- susceptible staphylococcus aureus,
Staphylococcus 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 Streptococcus
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(μg/ml) for doripenem and three
other carbapenems tested against Gram-positive pathogens
Strains (NO.)
Doripenem
Imipenem
Meropenem
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
0.125
0.125
Methicillin- resistant
Staphylococcus epidermidis(27)
32
128
64
≤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
4
1
8
8
Streptococcus pyogenes(42)
Enterococcus faecalis(26)
MIC90 : MIC at which 90% of the strains were inhibited
Biapenem
128
2. Antibacterial activity against GDoripenem 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. aeruginosa （铜绿假单胞菌）
Comparison of the MIC90(μg/ml) for doripenem and three othe
carbapenems tested against Gram-negative pathogens
Strains (NO.)
E. Coli (30)
Doripenem
0.032
Imipenem
Meropenem
Biapenem
0.125
0.016
0.063
Klebsiella pneumoniae(30) 0.063
0.25
0.032
0.125
Aerobacter cloacae(30)
0.063
0.5
0.063
0.125
P. aeruginosa (83)
2
8
Proteus mirabilis(27)
0.5
4
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
2
0.125
4
2
3. Antibacterial activity against P. aeruginosa

Pseudomonas, a Gram-negative bacterium, is
one of the leading causes of resistant hospitalacquired 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 within
zones of growth 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 by 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
Ideal 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 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 intraabdominal and complicated urinary tract 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)
licensed to Peninsula
Pharmaceuticals Inc.
(Alameda, CA, USA)
Doripenem has received
fast-track designation
from the U.S. FDA for
the treatment of
nosocomial pneumonia,
including ventilatorassociated pneumonia
“Finibax 0.25g IV Solution”
launched in Japan in 2005
a subsidiary of
Johnson & Johnson, in
2005
In phase III trials for
treatment of
complicated intraabdominal infection and
complicated lower
urinary tract 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:
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.
Market prospects
Now carbapenem in the drug market share
is rising, 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 practice 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.
References
4. Shihomi Sakyo, Haruyoshi Tomita, Koichi Tanimoto, Shuhei Fujimoto, Yasuyoshi
Ike. Potency of Carbapenems for the Prevention of Carbapenem-Resistant
Mutants of Pseudomonas aeruginosa. J. Antibiot. 59(4): 220–228, 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
[1]Ronald N. Jones,1,2* Holly K. Huynh,1 and Douglas J. Biedenbach1 Activities of
Doripenem (S-4661) against Drug-Resistant Clinical Pathogens
[2] Shazad Mushtaq,1 Yigong Ge,2 and David M. Livermore1 Comparative
Activities of Doripenem versus Isolates, Mutants, and Transconjugants of
Enterobacteriaceae and Acinetobacter spp. with Characterized _-Lactamases
[3] David Leif Anderson DORIPENEM Medical Information Department, Prous
Science, Barcelona, Spain
[4] Ronald N. Jones1,2*, Holly K. Huynh1, Douglas J. Biedenbach1, Thomas R.
Fritsche1 and Helio S. Sader1 Doripenem (S-4661), a novel carbapenem:
comparative activity
against contemporary pathogens including bactericidal action and preliminary in
vitro methods evaluations
[5] THYE DA, KILFOIL T, LEIGHTON A, WIKLER M. Doripenem: a Phase 1 Study
to Evaluate Safety, Tolerability and Pharmacokinetics in a Western Healthy
Volunteer Population.
[6] Yoshitsugu Nakajima, Minoru Mizobuchi, Masahiro Nakamura, Hidetoshi Takagi,
Haruhisa Inagaki, Goro Kominami, Masahiro Koike, and Toshiro Yamaguchi
MECHANISM OF THE DRUG INTERACTION BETWEEN VALPROIC ACID AND
CARBAPENEM ANTIBIOTICS IN MONKEYS AND RATS
References
1.张爱艳 朱雪焱 袁哲东 多尼培南的合成 中国医药工业杂志
2006, Vol37, No.6 p361-363
2.王建伟 黄娟 吴勇 王光明 Doripenem 关键中间体的合成
工艺研究 中国抗生素杂志 2006 年12月第31卷 第12期
p746-748