Design and synthesis of 5-[(2-chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001), a novel inhibitor of p38 MAP kinase with reduced side effects based on the antedrug concept

Hasumi, Koichi; Sato, Kimiyasu; Saito, Takahisa; Kato, Jun‐ya; Shirota, Kenji; Sato, Jun; Suzuki, Hiroyuki; Ohta, Shuji

doi:10.1016/j.bmc.2014.05.045

Cited by 16 publications

(16 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent efforts have focused on the development of drugs that exhibit reduced severe side effects as well as mechanisms that provide potent non-toxic targeted treatment of a specific tissue [117,120,121]. These studies involved the identification of p38α/βMAPK “inhibitors that show prodrug or antedrug properties; The prodrug properties involve an inactive compound that undergoes metabolic transformation-activation in vivo to provide an active drug to a specific targeted tissue.…”

Section: The Design and Mode Of Administration Of Inhibitors Of P3mentioning

confidence: 99%

“…The active antedrug is easily administered (orally) to the gut and is rapidly inactivated systemically. It ameliorates experimental colitis induced by dextran sulfates in mice and 2,4,6,-trinitro enzone sufonic in rats [120]. The antedrug design of AKP-001 facilitates its rapid metabolism to an inactive form, M1, through first-pass metabolism in the intestine and liver after oral administration (Figure 9.…”

Section: The Design and Mode Of Administration Of Inhibitors Of P3mentioning

confidence: 99%

See 1 more Smart Citation

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

Menon¹,

Papaconstantinou²

2016

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

Introduction Spontaneous preterm birth (PTB) and preterm premature rupture of the membranes (pPROM) remain as a major clinical and therapeutic problem for intervention and management. Current strategies, based on our knowledge of pathways of preterm labor, have only been effective, in part, due to major gaps in our existing knowledge of risks and risk specific pathways. Areas covered Recent literature has identified physiologic aging of fetal tissues as a potential mechanistic feature of normal parturition. This process is affected by telomere dependent and p38 mitogen activated protein kinase (MAPK) induced senescence activation. Pregnancy associated risk factors can cause pathologic activation of this pathway that can cause oxidative stress induced p38 MAPK activation leading to senescence and premature aging of fetal tissues. Premature aging is associated with sterile inflammation capable of triggering preterm labor or preterm premature rupture of membranes. Preterm activation of p38MAPK can be considered as a key contributor to adverse pregnancies. Expert Opinion This review considers p38MAPK activation as a potential target for therapeutic interventions to prevent adverse pregnancy outcomes mediated by stress factors. In this review, we propose multiple strategies to prevent p38MAPK activation and its functional effects.

show abstract

Section: The Design and Mode Of Administration Of Inhibitors Of P3mentioning

confidence: 99%

Section: The Design and Mode Of Administration Of Inhibitors Of P3mentioning

confidence: 99%

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

Menon¹,

Papaconstantinou²

2016

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

show abstract

“…M2 had no inhibitory effect on any of the p38 MAPK isoforms, and IC 50 values were greater than 10 mM for both isozymes (unpublished data). The inhibitory activity of the metabolites was 30-fold higher than that of AKP-001 (IC 50 : 10.9 and 326 nM for p38a and p38b) (Hasumi et al, 2014). The observed unbound C max of M1 and M2 after oral dosing of AKP-001 at 70 mmol/kg was 56.1 nM and 8.47 nM (Tables 1 and 5), which was sufficiently low compared with the IC 50 values.…”

Section: Discussionmentioning

confidence: 84%

“…The safety of metabolites should be determined for a risk assessment of ante-drug. Metabolite M1 had a weak inhibitory potential for p38 MAPK isozymes and the IC 50 values of M1 for p38a and p38b were 0.792 mM and 9.71 mM, respectively (Hasumi et al, 2014). M2 had no inhibitory effect on any of the p38 MAPK isoforms, and IC 50 values were greater than 10 mM for both isozymes (unpublished data).…”

Section: Discussionmentioning

confidence: 90%

“…1) is a novel p38 MAPK inhibitor synthesized by ASKA Pharmaceutical Co. Ltd. that potently inhibits the ability of p38a and p38b to phosphorylate target proteins (IC 50 = 10.9 and 326 nM, respectively). AKP-001 ameliorated experimental colitis induced by dextran sulfate sodium in mice and by 2,4,6-trinitrobenzene sulfonic acid in rats (Hasumi et al, 2014). AKP-001 was designed according to the ante-drug concept, and is quickly metabolized to an inactive form, M1 (Fig.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Analysis of the Disposition of a Novel p38 MAPK Inhibitor, AKP-001, and Its Metabolites in Rats with a Simple Physiologically Based Pharmacokinetic Model

et al. 2014

Self Cite

View full text Add to dashboard Cite

5-[(2-Chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001) is a potent p38 mitogen-activated protein kinase inhibitor that is being developed to specifically target the intestines for the treatment of inflammatory bowel disease. According to the ante-drug concept, AKP-001 was designed to be metabolized to inactive forms via the first-pass metabolism to avoid undesirable systemic exposure. The purpose of this study is to investigate the pharmacokinetic characteristics of AKP-001 and its metabolites (M1 and M2) in rats, utilizing a simple physiologically based pharmacokinetic (PBPK) model. In vitro metabolic activity of AKP-001 in the S9 fraction of rat liver was examined, and plasma concentration-time profiles were developed following intravenous and/or oral administration of AKP-001 and its metabolites. AKP-001 was primarily metabolized to M1; however, M2 was not detected in liver S9 fractions. In accordance with this observation in vitro, M2 was detected in plasma after oral dosing of AKP-001 with a lag time of 1.5 hours, but not after intravenous dosing. To analyze pharmacokinetics in rats in vivo, a simple PBPK model was developed by simultaneous fitting of the plasma concentrations after treatment with AKP-001 and its metabolites. The observed plasma concentration-time profiles of AKP-001 and metabolites were described by the model adequately. Intestinal and systemic exposures of AKP-001 were simulated using the model to assess the relationship between pharmacokinetics and efficacy/safety. Model analysis suggested that oral bioavailability of intestinetargeting ante-drugs should be low to avoid systemic side effects. The pharmacokinetic properties of AKP-001 meet this criterion owing to extensive first-pass metabolism.

show abstract

Synthesis of Bi‐ and Polyfunctional Isoxazoles from Amino Acid Derived Halogenoximes and Active Methylene Nitriles

et al. 2018

View full text Add to dashboard Cite

The reaction of chloroximes that have a protected amino group and active methylene nitriles under basic conditions has been shown to give functionalized 5‐aminoisoxazoles in yields of 37–81 %. This method has a broad substrate scope, including nitriles that contain either an electron‐withdrawing (i.e., CO2Me, CN, or SO2Me) or a heteroaryl group at the α‐position. Moreover, a malononitrile dimer was employed in analogous transformations, which led to the formation of polyfunctional isoxazolo[5,4‐b]pyridines. The selective removal of the protecting groups contained in the product demonstrated the utility of these compounds as advanced building blocks in early drug discovery programs.

show abstract

Design and synthesis of 5-[(2-chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001), a novel inhibitor of p38 MAP kinase with reduced side effects based on the antedrug concept

Cited by 16 publications

References 26 publications

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

Analysis of the Disposition of a Novel p38 MAPK Inhibitor, AKP-001, and Its Metabolites in Rats with a Simple Physiologically Based Pharmacokinetic Model

Synthesis of Bi‐ and Polyfunctional Isoxazoles from Amino Acid Derived Halogenoximes and Active Methylene Nitriles

Contact Info

Product

Resources

About