ACS Medicinal Chemistry Letters
Letter
Placebo-Controlled Studies in Subjects with Type 2 Diabetes. Diabetes,
Obes. Metab. 2012, 14, 709−716.
properties. Further optimization to improve overall PK profile
and reduce projected human dose will be reported in due
course.
(12) Shah, U. GPR119 agonists: A promising new approach for the
treatment of type 2 diabetes and related metabolic disorders. Curr.
Opin. Drug Discovery Dev. 2009, 12, 519−532.
ASSOCIATED CONTENT
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(13) Wood, H. B.; Szewczyk, J. W.; Huang, Y.; Adams, A. D.
Substituted cyclopropyl compounds, compositions containing such
compounds and methods of treatment. WO 2009129036 A1, 2009.
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S.; Howard, A. D.; Huang, Y.; Li, C.; Mosely, R.; Murphy, E.; Samuel,
R.; Santini, C.; Yang, M.; Zhang, Y.; Zhao, K.; Wood, H. B. Design of
potent and selective GPR119 agonists for type II diabetes. Bioorg. Med.
Chem. Lett. 2011, 21, 2665−2669.
S
* Supporting Information
Synthetic procedures and characterization data of selected
compounds, conditions for the biological assays, and protocol
for pharmacokinetic and pharmacodynamic studies. The
Supporting Information is available free of charge on the
(15) Unpublished results.
(16) For the composition of the FaSSIF, see Table 13 in Dressman, J.
B.; Amidon, G. L.; Reppas, C.; Shah, V. P. Dissolution Testing as a
Prognostic Tool for Oral Drug Absorption: Immediate Release Dosage
Forms. Pharm. Res. 1998, 15, 11−22.
(17) For an introduction to biorelevant media, such as fasted state
simulated intestinal fluid (FaSSIF), see: Galia, E.; Nicolaides, E.;
Horter, D.; Lobenberg, R.; Reppas, C.; Dressman, J. B. Evaluation of
various dissolution media for predicting in vivo performance of class I
and II drugs. Pharm. Res. 1998, 15, 698−705.
(18) FaSSIF solubility was used as one of the key parameters during
the optimization of this lead series since it was demonstrated that
dissolution testing in biorelevant media such as FaSSIF mimics the in
vivo situation more closely, which provides better in vitro/in vivo
correlation; see: Dressman, J. B.; Reppas, C. In vitro−in vivo
correlations for lipophilic, poorly water-soluble drugs. Eur. J. Pharm.
Sci. 2000, 11 (Suppl. 2), S73−S80.
(19) Oh, D. M.; Curl, R.; Amidon, G. Estimating the fraction dose
absorbed from suspensions of poorly soluble compounds in humans: a
mathematical model. Pharm. Res. 1993, 10, 264−270.
(20) Martinez, M.; Amidon, G. A mechanistic approach to
understanding the factors affecting drug absorption: a review of
fundamentals. J. Clin. Pharmacol. 2002, 42, 620−643.
(21) Rohrs, B. R. Biopharmaceutics Modeling and the Role of Dose
and Formulation on Oral Exposure. In Optimizing the “Drug-Like”
Properties of Leads in Drug Discovery; Borchardt, R. T., Hageman, M. J.,
Stevens, J. L., Kerns, E. H., Thakker, D. R., Eds; Springer: New York,
2006; Vol. IV, pp 151− 166.
(22) Wuelfing, W. P.; Daublain, P.; Kesisoglou, F.; Templeton, A.;
McGregor, C. Preclinical dose number and its application in
understanding drug absorption risk and formulation design for
preclinical species. Mol. Pharmaceutics 2015, 12, 1031−1039.
(23) Desai, D.; Wang, J.; Wen, H.; Li, X.; Timmins, P. Formulation
design, challenges, and development considerations for fixed dose
combination (FDC) of oral solid dosage forms. Pharm. Dev. Technol.
(24) Benet, L. Z.; Zia-Amirhosseini, P. Basic Principles of
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(25) Smith, D. A.; Beaumont, K.; Maurer, T. S.; Di, L. Volume of
AUTHOR INFORMATION
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Corresponding Author
*Phone: 732-594-0321. Fax: 732-594-9556. E-mail: ping_liu2@
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank Dr. Jeffrey J. Hale for insightful suggestions.
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