Design and synthesis of boron-containing PDE4 inhibitors using soft-drug strategy for potential dermatologic anti-inflammatory application

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 7, 2010, Pages 2270-2274

  Zhang, Yong Kang ^a   Plattner, Jacob J ^a   Akama, Tsutomu ^a   Baker, Stephen J ^a   Hernandez, Vincent S ^a   Sanders, Virginia ^a   Freund, Yvonne ^a   Kimura, Richard ^a   Bu, Wei ^a   Hold, Karin M ^a   Lu, Xiao Song ^b  

^a PFIZER INC   (United States)

^b NAEJA Pharmaceutical Inc   (Canada)

Author keywords

Anti inflammatory; Benzoxaborole; Dermatology; Phosphodiesterase; Soft drug

Indexed keywords

ANTIINFLAMMATORY AGENT; BENZOXABOROLE; BENZOXAZINE DERIVATIVE; BORON; CYTOKINE; DERMATOLOGICAL AGENT; EMETIC AGENT; ESTER; PHOSPHODIESTERASE IV INHIBITOR; ROLIPRAM; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTICLE; DERMATOLOGY; DRUG POTENCY; MALE; MOUSE; NONHUMAN; SINGLE DRUG DOSE; SYNTHESIS; VOMITING;

ANIMALS; ANTI-INFLAMMATORY AGENTS; BORON; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 4; EAR; EDEMA; HUMANS; MICE;

EID: 77949541990     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.02.010     Document Type: Article

References (23)

1. Currie G.P., Butler C.A., Anderson W.J., and Skinner C. Br. J. Clin. Pharmacol. 65 (2008) 803
2. Marx D., Tassabehji M., Heer S., Huettenbrink K.-B., and Szelenyi I. Pulm. Pharmacol. Ther. 15 (2002) 7
3. Boot J.D., De Haas S.L., Van Gerven J.M.A., De Smet M., Leathem T., Wagner J., Denker A., Miller D., Van Doorn M.B.A., Schoemaker R.C., Cohen A.F., and Diamant Z. Pulm. Pharmacol. Ther. 21 (2008) 573
4. Dini F.L., and Cogo R. Curr. Med. Res. Opin. 16 (2001) 258
5. Rxlist.com.
6. www.iddb3.com.
7. Fitzgerald M.F., and Fox J.C. Drug Discovery Today 12 (2007) 479
8. McKenna J.M., and Muller G.M. In: Beavo J., Francis S.H., and Houslay M.D. (Eds). Cyclic Nucleotide Phosphodiesterases in Health and Disease (2007), CRC/Taylor & Francis, Boca Raton 667-699
9. Giembycz M.A. In: Beavo J., Francis S.H., and Houslay M.D. (Eds). Cyclic Nucleotide Phosphodiesterases in Health and Disease (2007), CRC/Taylor & Francis, Boca Raton 649-665
10. Giembycz M.A. Br. J. Pharmacol. 155 (2008) 288
11. Spina D. Br. J. Pharmacol. 155 (2008) 308
12. Baker S.J., Zhang Y.-K., Akama T., Lau A., Zhou H., Hernandez V., Mao W., Alley M.R.K., Sanders V., and Plattner J.J. J. Med. Chem. 49 (2006) 4447
13. Fernando R., Mao W., Yaremchuk A., Tukalo M., Crépin T., Zhou H., Zhang Y.-K., Hernandez V., Akama T., Baker S.J., Plattner J.J., Shapiro L., Martinis S.A., Benkovic S.J., Cusack S., and Alley M.R.K. Science 316 (2007) 1759
14. Baker S.J., Akama T., Zhang Y.-K., Sauro V., Pandit C., Singh R., Kully M., Khan J., Plattner J.J., Benkovic S.J., Lee V., and Maples K.R. Bioorg. Med. Chem. Lett. 16 (2006) 5963
15. Akama, T., Baker, S. J., Zhang, Y.-K., Zhou, H., Hernandez, V., Sanders, V., Plattner, J. J. Abstracts, 65th Annual Meeting of the American Academy of Dermatology, Feb 2-6, 2007; Washington, DC, USA.
16. Akama, T., Freund, Y., Kimura, R., Baker, S. J., Zhang, Y.-K., Hernandez, V., Zhou, H., Sanders, V., Maples, K. R., Plattner, J. J. Abstracts, International Investigative Dermatology 2008 Conference, May 14-17, 2008, Kyoto, Japan.
17. Akama T., Baker S.J., Zhang Y.-K., Hernandez V., Zhou H., Sanders V., Freund Y., Kimura R., Maples K.R., and Plattner J.J. Bioorg. Med. Chem. Lett. 19 (2009) 2129
18. Bodor N. Trends Pharmacol. Sci. 3 (1982) 53
19. Bodor N. Adv. Drug Res. 13 (1984) 255
20. 2.
21. 2EDTA, purchased from Bioreclamation) and in phosphate buffer saline (PBS, pH 7.4, purchased from Sigma). To two plates (one for time 0 and the other for time 60 min), 90 μL of plasma was added to each well. To other two plates, 90 μL of PBS was added. Ten microliters of each compound PBS solution (50 μM) was added to the well resulting in 5 μM final sample concentration. Time 60 min plate was placed in water bath set at 37 °C with mild shaking and time 0 min plate was left on ice and was quenched with 300 μL of internal standard working solutions (ISWS, 0.1 μg/mL in acetonitrile or methanol depending on the structures of compounds tested) on ice after the preparation. After incubation for 1 h, the time 60 min plate was placed on ice and then 300 μL of ISWS was added to each well. Both plasma plates were vortexed and then centrifuged at approximate 1800 rpm for 10 min. To a 96-well autosampler plate, 200 μL of supernatant of all samples were transferred and proceed for LC/MS/MS analysis (MS instrument API3000 assembled with Shimadzu LC-10AD system). Each compound was incubated and processed in triplicate.
22. max of 4.39 μg/mL and 12.7 μg/mL were achieved at 0.25 h for po and 0.25 h for sc, respectively. The mean bioavailability was approximately 10.8% for po dosing and 97.8% for sc dosing. The measurable acid was observed and its profiles were similar to its corresponding ester in all dosing groups. The acid was not quantified and no pharmacokinetics parameters were generated.
23. (a) Emetic activities of rolipram and ester 2 were tested with the procedure as described below. Male animals (Suncus murinus, body weights 50-70 g, purchased from CLEA Japan Inc.) were administered orally with rolipram at 10 mg/kg or ester compound 2 at 10, 30 and 100 mg/kg in 1% carboxymethylcellulose (1% CMC) at a dosing volume of 10 mL/kg. Then animals were observed for retching and emetic responses for 90 min post-dosing. A positive emetic episode was defined as disgorgement of the stomach contents generally preceded by retching and its occurrence in one or more of 3 or 4 test animals was considered significant. Additionally, the number, onset and duration of emetic episodes were recorded; (b) Structure of rolipram [4-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrrolidin-2-one, C Log P = 1.715, molecular weight = 275.34]:{A figure is presented}