Doripenem - A New Broad-Spectrum Carbapenem Antibiotic

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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-hydroxyethylgroup, 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 a

rise 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

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。

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 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-7-oxo-3[[(3S,5S)-5-(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid mon

ohydrate

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-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-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).

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）。

NH

COOH

HOCH3OH SOCl2

NH

COOMe

HO(Boc)2O

CH3SO2ClCOOMeN

MsO

NOH

MsO

KBH4 ZnCl2CH3COSK

NOH

AcS

(C6H5)3P

Boc-NHSO2NH2N

NSO2NH2

AcSCH3ONa

CH3OHN

NSO2NH2

HS

NCO2PNB

OP(OPh)2

O

HOH

OH

(i-Pr)2NEt NCO2PNB

S

O

HOH

H

NNSO2NH2

AlCl3/OMe

NS

O

HOH

COOH

H

NH

NHSO2NH2N

CO2PNB

S

O

HOH

H

NH

NHSO2NH2

Pd/C

,

.HCl

2

1.

2.

Boc

Boc

/3

Boc

54

Boc

Boc

Boc

Boc

6 7

Boc

Boc

9

10 1

8

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

Step 1

NH

COOH

HOCH3OH SOCl2

NH

COOMe

HO(Boc)2O

CH3SO2ClCOOMeN

MsO,

.HCl

2

1.

2.

Boc

3

-Boc: 叔丁氧羰基 , 保护氨基-Ms: 甲磺酰基 , 活化羟基

Step 2

COOMeN

MsO

NOH

MsO

KBH4 ZnCl2CH3COSK

NOH

AcS

Boc

3

Boc

/

Boc

54

酯基还原 , 还原剂的选择 SN2 反应 ,4 位发生构型反转

Step 3

(C6H5)3P

Boc-NHSO2NH2N

NSO2NH2

AcSCH3ONa

CH3OHN

NSO2NH2

HS

NOH

AcS

Boc

Boc

Boc

Boc

6 7

Boc

5

Boc-NHSO2NH2: N- 叔丁氧羰基氨磺酰胺 Mitsunobu Reaction

醇解脱去乙酰基

Step 4

NNSO2NH2

HS

NCO2PNB

OP(OPh)2

O

HOH

OH

(i-Pr)2NEt NCO2PNB

S

O

HOH

H

NNSO2NH2Boc

Boc

7 Boc

Boc

9

8

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

NCO2PNB

S

O

HOH

H

NNSO2NH2

AlCl3/OMe

NCO2PNB

S

O

HOH

H

NH

NHSO2NH2

Boc

Boc

9 10

脱掉 -Boc 保护基

Step 6

NS

O

HOH

COOH

H

NH

NHSO2NH2N

CO2PNB

S

O

HOH

H

NH

NHSO2NH2

Pd/C

10 1

脱掉 -PNB( 对硝基苄基 )

氢解反应

Mitsunobu Reaction

N NEtO OEt

O OR'3P N NEtO OEt

O O

R'3P+

HXN NHEtO OEt

O O

R'3P+

R2OHR'3P+ OR2 N

HEtO

O

NH

OEt

O

R'3P O R2X-

+

. X- .

X- +

+

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 ot

her beta-lactam antibiotics : combining with bacterial penicillin-binding prot

ein (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, 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 imi

penem, strong in contrast to other drugs

Comparison of the MIC90(μg/ml) for doripenem and three oth

er 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

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 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. aeruginosa （铜绿假单胞菌）

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 4MIC90 : MIC at which 90% of the strains were inhibited

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.

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.

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 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.

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 subsidiary 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 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.

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.

Market prospects

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 activityagainst 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