Doripenem - A New Broad-Spectrum Carbapenem Antibiotic Group

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Doripenem - A New Broad-Spectrum Carbapenem
Antibiotic

• Group Member 0440213 0440216
• 0441515 0441523

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SAR of doripenem
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From Penicillins To Carbapenems
????????? ????(???,Thienamycin)???
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Carbapenem before Doripenem
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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

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Analysis of SAR

• Mechanism
• Stability
• b-lactamase stability
• stability against human renal
  dehydropeptidase I (DHPI)
• Antimicrobial features
• Toxic effects

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Mechanism

• Like all beta-lactam antimicrobial agents,
  carbapenems act by inhibiting bacterial cell wall
  synthesis by binding to and inactivating
  penicillin-binding proteins (PBPs).

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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-???????????????B-?????????????????? 6-??
??????????a-?????,?????????????,??B-??????B-??????
?
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Human renal dehydropeptidase1(DHP1) stability
1-beta-methyl side chain provides resistance to
the renal enzyme DHP1.
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Antimicrobial Features
A particular feature, the side chain at position
2 sulfamoylaminomethyl group.

• I.??B-?????????,???????????????????,??????,?1?????
  ??????,???sp3????????????,???C2?C3??????,?????????
  ??,???B-?????????,?????????????????????
• II.2???????????,??????G-????????
• III. C-3???????,????????????,???G-??????????????

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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.

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Synthesis of doripenem
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• (1R,5S,6S)-6-(1R)-1-???-2-(3S,5S)-5-???????
  ???-3-???-1-??-1-??-2-???-3-??

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• ()-(4R,5S,6S)-6-(1R)-1-hydroxyethyl-4-m
  ethyl-7-oxo-3(3S,5S)-5-(sulfamoylaminomethyl)pyr
  rolidin-3-ylthio-1-azabicyclo 3.2.0
  hept-2-ene-2-carboxylic acid monohydrate

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• 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-diphenoxypho
  sp 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 yield of 50.8. The overall yield was
  about 26 (based on trans-4-hydroxy-L-proline).
• ??-4-??-L-?????????????SN2???
  Mitsunobu???????(2S,4S)-1-??????????)??-4-?????(7)
  ,??50.8?7?(1R,5S,6S)-6-(1R)-1-???-2-???????-1-?
  ?-1-??-2-???-3-???????(8)??????,??????,??50.5(?7?
  )??????26(???-4-??-L-????)?

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• Step 1 Step 2 Step 3 Step 4
  Step 5 Step 6 NEXT

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Step 1

• -Boc ?????,????
• -Ms????,????

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Step 2

• ????,??????
• SN2??,4???????

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Step 3

• Boc-NHSO2NH2 N-?????????
• Mitsunobu Reaction
• ???????

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Step 4

• ???8(1R,5S,6S)-6-(1R)-1-???-2-???????-1-??-1
  -??-2-???-3-???????(MAP,??)
• ????

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Step 5

• ??-Boc???

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Step 6

• ??-PNB(?????)
• ????

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Mitsunobu Reaction
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Research is a difficult job for us
to challenge. Fighting!

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Comparison of doripenem and other carbapenems
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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
  beta-lactamase and kidney dehydrogenation
  endopeptidase (DHP) -1.

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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

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• 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

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Comparison of the MIC90(µg/ml) for doripenem and
three other carbapenems 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
0.125 0.125
Methicillin- resistant Staphylococcus
epidermidis(27)
32 128
64 128
0.004 0.008
0.008 0.008
Streptococcus pyogenes(42)
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
Enterococcus faecalis(26)
MIC90 MIC at which 90 of the strains were
inhibited
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2. Antibacterial activity against G-

• Doripenem is sensitive to many G- bacteria, such
  as
• E. coli
• Klebsiella pneumoniae (???????)
• Enterobacteriaceae (???)
• Proteus mirabilis (??????)
• Proteus vulgaris (??????)
• Haemophilus influenza (??????)
• P. aeruginosa (??????)

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Comparison of the MIC90(µg/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
  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

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3. Antibacterial activity against P. aeruginosa

• Pseudomonas, a Gram-negative bacterium, is
  one 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.

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Presence of carbapenem-resistant mutants
withinzones 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.

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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

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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.

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Market prospects
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Market prospects

• Ideal antibiotics
• safe, efficient, broad-spectrum

The situation for antibiotics isas they used in
the large clinical application, resistant of
bacteria has become increasing serious.
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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.
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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 tract infections.
• The nosocomial pneumonia indication for
  doripenem
• had been granted "fast-track" status by the
  FDA in Dec 2006.

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Developing Process

• Shionogi Co., Ltd. (Osaka, Japan)

Finibax 0.25g IV Solution launched in Japan in
2005
a subsidiary of Johnson Johnson, in 2005
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 ventilator-associated
pneumonia
In phase III trials for treatment of complicated
intra-abdominal infection and complicated lower
urinary tract infections in 2006.12
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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.

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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.
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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 .

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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.

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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) 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
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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 Comparative Activities of
Doripenem versus Isolates, Mutants, and
Transconjugants of Enterobacteriaceae and
Acinetobacter spp. with Characterized
_-Lactamases3 David Leif Anderson DORIPENEM
Medical Information Department, Prous Science,
Barcelona, Spain4 Ronald N. Jones1,2, Holly
K. Huynh1, Douglas J. Biedenbach1, Thomas R.
Fritsche1 and Helio S. Sader1 Doripenem (S-4661),
a novel carbapenem comparative activityagainst
contemporary pathogens including bactericidal
action and preliminary in vitro methods
evaluations5 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
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References
1.??? ??? ??? ??????? ???????? 2006, Vol37, No.6
p361-363 2.??? ?? ?? ??? Doripenem ????????????
??????? 2006 ?12??31? ?12? p746-748
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