Makoto Sunagawa

Bio: Makoto Sunagawa is an academic researcher from Kwansei Gakuin University. The author has contributed to research in topics: Alkyl & Antibacterial agent. The author has an hindex of 19, co-authored 112 publications receiving 1205 citations. Previous affiliations of Makoto Sunagawa include Dainippon Sumitomo Pharma Co., Ltd..

Stability of meropenem and effect of 1 beta-methyl substitution on its stability in the presence of renal dehydropeptidase I.

Abstract: The stability of meropenem in the presence of renal dehydropeptidase I (DHP-I) varied extremely with the animal source of the enzyme. Meropenem, compared with imipenem, was rather easily hydrolyzed by DHP-Is from mice, rabbits, and monkeys, while it showed a higher resistance to guinea pig and beagle dog DHP-Is. In addition, meropenem was four times more resistant than imipenem to human DHP-I. The 1 beta-methyl substituent on carbapenems, i.e., meropenem and 1 beta-methyl imipenem, made them considerably more resistant to mouse and swine DHP-Is than the 1-unsubstituted derivatives are.

Structural Features Resulting in Convulsive Activity of Carbapenem Compounds: Effect of C-2 Side Chain.

Abstract: The neurotoxicity of meropenem was much lower than that of both imipenem and panipenem after intraventricular administration to mice. To clarify the major structural features responsible for the induction of convulsions by carbapenem antibiotics, the structure-activity relationship on convulsant activity was investigated in N-acetyl-2-pyrroline and cyclopentene derivatives which correspond to the 5-membered ring containing the C-2 side chain of carbapenem antibiotics. Among these derivatives, compounds with strong basicity in the side chain showed convulsant activity similar to that of the parent carbapenem compounds. In addition to the strength of the basicity of the amino group, the distance from the carboxyl to the amino group and steric crowding around the amino group also appeared to play an important role in the induction of convulsions. The results of gamma aminobutyric acid (GABAA) receptor binding assays indicated that the induction of convulsions was caused predominantly by the inhibition of GABAA-mediated inhibitory transmission. However, the in vivo convulsant activity of some of these compounds did not correlate with their in vitro inhibitory effect on GABAA receptor binding.

Carbapenem compound in crystalline form, and its production and use

Abstract: (4R,5S,6S 8R,2'S,4'S)-3-[4-(2-Dimethylaminocarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid of the formula: ##STR1## in a crystalline form, which is useful as an antibiotic agent.

Stability of a 1β-Methylcarbapenem Antibiotic, Meropenem (SM-7338) in Aqueous Solution

Abstract: The stability and the degradation products of 1β-methylcarbapenem, meropenem in aqueous solution were investigated. In pH 4-8 dilute solution pseudo-first-order degradation was observed, and good stability of meropenem in aqueous solution was demonstrated by the effect of 1β-methyl group against hydrolysis of β-lactam ring. As degradation products, the β-lactam hydrolyzed product and the dimer product resulting from intermolecular aminolysis of β-lactam ring by the amine of the second molecule were described.

Carbapenems: Past, Present, and Future

Abstract: In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the β-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most β-lactamases, in some cases act as "slow substrates" or inhibitors of β-lactamases, and still target penicillin binding proteins. This "value-added feature" of inhibiting β-lactamases serves as a major rationale for expansion of this class of β-lactams. We describe the initial discovery and development of the carbapenem family of β-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.

Inhibitors of farnesyl protein transferase

Abstract: The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras