Fumiyuki Shirai

Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems Part IV. 2-Alkyl substituents containing cationic heteroaromatics linked via a C–C bond

The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrolidinylthio-beta-methylcarbapenems containing a variety of cationic heteroaromatic substituents linked via a C-C bond is described. As a result of these studies, we selected FR21818 (In) as a candidate compound for development. FR21818 exhibited a well balanced spectrum of antibacterial activity, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), excellent urinary recovery, good stability against renal dehydropeptidase-I (DHP-I). no antigenicity and mutagenicity, weak toxicities, and good efficacy and therapeutic effect on mice systemic infections. Affinities to PBPs, permeability of outer membrane, and plasma levels in mice, dog, and cynomolgous monkey of FR21818 are also reported.

Effects of non-steroidal anti-inflammatory drugs on Aβ deposition in Aβ1–42 transgenic C. elegans

Although epidemiological studies have shown that long-term treatment with non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimers disease (AD), the mechanism(s) by which NSAIDs reduce the risk of AD remain to be determined. As C. elegans possess neither inflammatory cells nor the arachidonate cascade, we could evaluate the effects of NSAIDs on amyloid beta (Abeta) deposition in the absence of immune cells using Abeta-transgenic C. elegans. For this purpose, we established a strain of Abeta-transgenic C. elegans in which thioflavin S-reactive deposits are reproducibly detectable by confocal microscopy. Among the NSAIDs examined, ibuprofen and naproxen reduced the number of thioflavin S-reactive deposits. Furthermore, ibuprofen and naproxen neither affect the thioflavin S binding to Abeta nor Abeta expression in transgenic C. elegans. These data suggest that ibuprofen and naproxen, the most frequently used NSAIDs for the treatment of AD, have an inhibitory effect on Abeta deposition that is independent of the arachidonate cascade and cellular immune systems.

Orally active cephalosporins: synthesis, structure-activity relationships and oral absorption of 3-[(E) and (Z)-2-substituted vinyl]-cephalosporins.

A series of 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamid o]-3-[(E)- and (Z)-2-substituted vinyl]-3-cephem-4-carboxylic acids was designed and synthesized using palladium-catalyzed coupling reactions of a 3-methanesulfonyloxy-3-cephem and an E substituted vinyl stannane or Wittig reaction of a 3-triphenylphosphoniummethyl cephem and an aldehyde as a key step. These compounds were evaluated for in vitro antibacterial activity and oral absorption in rats. A number of them exhibited excellent antibacterial activity against both gram-positive and gram-negative bacteria including Haemophilus influenzae. Among them, FR86524 (2j). having a (Z)-2-(3-pyridyl)vinyl moiety at the C-3 position, had the most well balanced activity. Although FR86254 exhibited low oral absorption, the pivaloyloxymethyl ester (23) of FR86524 showed improved oral absorption.

Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems. Part III:

Abstract The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrolidinylthio-β-methylcarbapenems containing a variety of cationic heteroaromatic substituents is described. As a result of these studies, we uncovered a relationship between in vitro antibacterial activity and the length of the alkyl spacer part, and discovered FR20950 ( 1c ) Download high-res image (74KB) Download full-size image Scheme 3 . Synthetic route to novel carbapenems. Reagents and conditions: (i) NaOMe, MeOH, (or TFA, Et 3 SiH), then 24 , i Pr 2 EtN, DMAC, MeCN; (ii) MeI, Me 2 CO or THF; (iii) ICH 2 CONH 2 , Me 2 CO; (iv) I(CH 2 ) 3 NHAoc, DMF; (v) MeOTf, CH 2 Cl 2 ; (vi) FSO 3 Me, CH 2 Cl 2 ; (vii) Pd(PPh 3 ) 4 , PPh 3 , THF–EtOH, n Bu 3 SnH or morpholine; (viii) Pd(OH) 2 -C, H 2 , THF–phosphate buffer (pH 6.5). , containing a two methylene spacer moiety and an imidazolio group, which possesses a balanced spectrum of antibacterial activity, including Pseudomonas aeruginosa and Methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, FR20950 exhibited excellent urinary recovery, and comparable stability against renal dehydropeptidase-I (DHP-I) to Biapenem. DHP-I stability could be improved by introduction of a substituent on to the imidazole ring.

Optimization of 2,4-diamino-5-fluoropyrimidine derivatives as protein kinase C theta inhibitors with mitigated time-dependent drug-drug interactions and P-gp liability.

Protein kinase C theta (PKCθ) plays a critical role in T cell signaling and has therapeutic potential for T cell-mediated diseases such as transplant rejection and rheumatoid arthritis. Here, a series of 2,4-diamino-5-fluoropyrimidine derivatives were prepared and evaluated for their inhibition of PKCθ. Of these compounds, 14f was found to exhibit potent PKCθ inhibitory activity and significantly weak CYP3A4 time-dependent inhibition (TDI) and P-glycoprotein (P-gp) liability.

Activity cliff for 7-substituted pyrrolo-pyrimidine inhibitors of HCK explained in terms of predicted basicity of the amine nitrogen.

We previously reported the structure-based design of a highly potent hematopoietic cell kinase (HCK) inhibitor, a pyrrolo-pyrimidine compound designated RK-20449, for treatment of recurrent leukemia. Herein we report the synthesis and structure-activity relationships of some amino acid derivatives of 7-substituted pyrrolo-pyrimidine. Although these derivatives had the same predicted binding conformation as RK-20449, their IC50 values were 100-1000 times larger than that of the parent compound. We assumed that the basicity of the amine nitrogen, which formed an ionic bond with Asp348 of HCK, markedly affected inhibitory activity against HCK. The pKa values of the nitrogen were predicted by means of an ab initio quantum mechanical method, and complexes of the derivatives with HCK were analyzed by X-ray crystallography. We observed a significant correlation between the predicted pKa and IC50 values, and the crystal structures of the less potent derivatives showed various types of defects around the ionic bond.

Identification of pyrrolo[2,3-d]pyrimidines as potent HCK and FLT3-ITD dual inhibitors

A series of novel pyrrolo[2,3-d]pyrimidines were synthesized by introducing 15 different amino acids to 7-cyclohexyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine. Compounds with potent activities against HCK and FLT3-ITD were evaluated in viability studies with acute myeloid leukemia cell line MV4-11. Our structure activity relationship analyses lead to the identification of compound 31, which exhibited potent HCK and FLT3-ITD inhibition and activity against the MV4-11 cell line.