Highly potent PDE4 inhibitors with therapeutic potential

Ochiai, Hiroshi; Ohtani, Tazumi; Ishida, Akiharu; Kusumi, Kensuke; Kato, Masashi; Kohno, Hiroshi; Odagaki, Yoshihiko; Kishikawa, Katsuya; Yamamoto, Sachiko; Takeda, Hiroshi; Obata, Takaaki; Nakai, Hisao; Toda, Masaaki

doi:10.1016/j.bmc.2004.06.032

Cited by 14 publications

(9 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the desired amines for reductive amination was synthesized as shown in Scheme . Reaction of the Boc derivative of diethanolamine with acetic anhydride gave the diacetate 1 . Exposure of the latter to TFA resulted in the diacetate of diethanolamine ( 2 ), a known compound previously prepared as the hydrochloride salt by an alternative route…”

Section: Resultsmentioning

confidence: 99%

Tailoring a Bacteriochlorin Building Block with Cationic, Amphipathic, or Lipophilic Substituents

et al. 2008

View full text Add to dashboard Cite

Bacteriochlorins are attractive candidates for photodynamic therapy (PDT) of diverse medical indications owing to their strong absorption in the near-infrared (NIR) region, but their use has been stymied by lack of access to stable, synthetically malleable molecules. To overcome these limitations, a synthetic free base 3,13-dibromobacteriochlorin (BC-Br(3)Br(13)) has been exploited as a building block in the synthesis of diverse bacteriochlorins via Pd-mediated coupling reactions (Sonogashira, Suzuki, and reductive carbonylation). Each bacteriochlorin is stable to adventitious dehydrogenation by virtue of the presence of a geminal dimethyl group in each pyrroline ring. The target bacteriochlorins bear cationic, lipophilic, or amphipathic substituents at the 3- and 13- (beta-pyrrolic) positions. A dicarboxybacteriochlorin was converted to amide derivatives via the intermediate diacid chloride. A diformylbacteriochlorin was subjected to reductive amination to give aminomethyl derivatives. A set of 3,5-disubstituted aryl groups bearing lipophilic or amphipathic groups was introduced via Suzuki coupling. Altogether 22 free base bacteriochlorins have been prepared. Eight aminoalkylbacteriochlorins were quaternized with methyl iodide at two or four amine sites per molecule, which resulted in water solubility. Each bacteriochlorin exhibits a Q(y) absorption band in the range of 720-772 nm. The ability to introduce a wide variety of peripheral functional groups makes these bacteriochlorins attractive candidates for diverse applications in photomedicine including PDT in the NIR region.

show abstract

Section: Resultsmentioning

confidence: 99%

Tailoring a Bacteriochlorin Building Block with Cationic, Amphipathic, or Lipophilic Substituents

et al. 2008

View full text Add to dashboard Cite

show abstract

“…These studies are important because hydroxamic acids have several biological activities. For example, they are inhibitors of secretases involved in Alzheimer's disease and blood pressure regulation, chemotherapeutic agents, anti-inflammatory agents for the treatment of asthma and rheumatoid arthritis, antimalarial agents, iron chelators, and siderophores 11b. Furthermore it has recently been shown that N -hydroxy peptides react readily with α-keto acids to form amides .…”

Section: Introductionmentioning

confidence: 99%

Oxidation of Peptides by Methyl(trifluoromethyl)dioxirane: The Protecting Group Matters

Rella

Williard

2006

J. Org. Chem.

View full text Add to dashboard Cite

Representative Boc protected and acetyl protected peptide methyl esters bearing alkyl side chains undergo effective oxidation using methyl(trifluoromethyl)dioxirane (1b) under mild conditions. We observe a protecting group dependency in the chemoselectivity displayed by the dioxirane 1b. N-hydroxylation occurs in the case of the Boc protected peptides, side chain hydroxylation takes place in the case of acetyl protected peptides. Both are attractive transformations since they yield derivatized peptides that serve as valuable synthons.

show abstract

“…One approach adopted was to use a 4-difluoromethoxy group in place of the methoxy group with the idea of improved metabolic stability (entries 24–28 and 33–35, Table 2). 27,28 It turned out that these 4-difluoromethoxy compounds were also 2- to 14-fold more potent than the corresponding 4-methoxy substituted compounds (entries 14, 16, 18–20, and 37, Table 2). Within this series, the substituent effect at the 3-position was also studied.…”

Section: Resultsmentioning

confidence: 98%

“…Therefore, the synthesis started with the alkylation of 1 at either the 3- or 4-position (Scheme 1). In one series, a difluoromethyl group needed to be attached to the 4-position, which was achieved through the alkylation of 3,4-dihydroxybenzaldehyde using chlorodifluoroacetate to give 4-difluoromethoxy-3-hydroxybenzaldehyde 2a in 45% yield and 3,4-bis(difluoromethoxy)benzaldehyde 3n in 20% yield 27,28. For the series with methyl substitution at either the 3- or 4-position of the catechol core, commercially available 3-hydroxy-4-methoxybenzaldehyde 2b or 4-hydroxy-3-methoxybenzaldehyde 2c was used as the starting material.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Structure−Activity Relationship, Molecular Modeling, and NMR Studies of a Series of Phenyl Alkyl Ketones as Highly Potent and Selective Phosphodiesterase-4 Inhibitors

et al. 2008

View full text Add to dashboard Cite

Phosphodiesterase 4 catalyzes the hydrolysis of cyclic AMP and is a target for the development of anti-inflammatory agents. We have designed and synthesized a series of phenyl alkyl ketones as PDE4 inhibitors. Among them, 13 compounds were identified as having submicromolar IC50 values. The most potent compounds have IC50 values of in the mid- to low-nanomolar range. Compound 5v also showed preference for PDE4 with selectivity of >2000-fold over PDE7, PDE9, PDE2, and PDE5. Docking of 5v, 5zf, and 5za into the binding pocket of the PDE4 catalytic domain revealed a similar binding profile to PDE4 with rolipram except that the fluorine atoms of the difluoromethyl groups of 5v, 5za, and 5zf are within a reasonable range for hydrogen bond formation with the amide hydrogen of Thr 333 and the long alkyl chain bears additional van der Waals interactions with His 160, Asp 318, and Tyr 159.

show abstract

Highly potent PDE4 inhibitors with therapeutic potential

Cited by 14 publications

References 29 publications

Tailoring a Bacteriochlorin Building Block with Cationic, Amphipathic, or Lipophilic Substituents

Tailoring a Bacteriochlorin Building Block with Cationic, Amphipathic, or Lipophilic Substituents

Oxidation of Peptides by Methyl(trifluoromethyl)dioxirane: The Protecting Group Matters

Design, Synthesis, and Structure−Activity Relationship, Molecular Modeling, and NMR Studies of a Series of Phenyl Alkyl Ketones as Highly Potent and Selective Phosphodiesterase-4 Inhibitors

Contact Info

Product

Resources

About