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Shen et al.
The dog TI could also be expressed in terms of blood levels,
as was done in the rat model. The FFA reduction caused by 1e
versus the plasma drug level is shown in Figure 5. On a drug
level basis, dog TI = Cmax(TDV)/EC50 (FFA), in which
Cmax(TDV) was the corresponding average maximal blood
level of compound at the threshold dose of vasodilation, and
the in vivo EC50 (FFA) was generated from the concentra-
tion-response plot (Table 5).
Through quantification of the TI in the rat and dog models,
1e has a larger therapeutic index than NA, which could be
attributed to different binding kinetics of compounds and/or
tissue distribution profiles. Besides excellent receptor activity
and PK profile, 1e was remarkably clean in 166 different
biological target counter-screening assays (IC50 > 10 μM)
and CYP inhibition (IC50 > 100 μM for CYP2C8, 2D6, and
3A4; IC50 = 39 μM for CYP2C9). Furthermore, 1e displayed
no preliminary safety issues in ancillary pharmacological
studies in CNS mouse, CV dog, GI motility, renal and
respiratory dog models. Lastly, the presence of the hydro-
xypyridine group in 1e did not introduce any in vivo or in vitro
covalent binding issues, which is a common concern for
bioactivated drugs containing a phenolic moiety.11
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ꢀ
ꢀ
ꢀ
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The preparation of 1e is summarized in Scheme 2. This
scalable and convergent route featured a nucleophilic aro-
matic substitution to afford 3, an efficient cyclization to
construct oxadiazole 9, and a Pd-catalyzed C-N bond for-
mation to generate intermediate 12.12
(6) Cheng, K.; Wu, T.-J.; Wu, K. K.; Sturino, C.; Metters, K.;
Gottesdiener, K.; Wright, S. D.; Wang, Z.; O’Neil, G.; Lai, E.;
Waters, M. G. Antagonism of the prostaglandin D2 receptor 1
suppresses nicotinic acid-induced vasodilationin mice and humans.
Proc. Natl. Acd. Sci. U.S.A. 2006, 103, 6682–6687.
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E.; Wu, K. K.; Wu, T.-J.; Cheng, K.; Wilsie, L. C.; Krsmanovic,
M. L.; Taggart, A. K.; Ren, N.; Cai, T.-Q.; Deng, Q.; Chen, Q.;
Wang, J.; Wolff, M. S.; Tong, X.; Holt, T. G.; Waters, M. G.;
Hammond, M. L.; Tata, J. R.; Colletti, S. L. Discovery of biaryl
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J. Med. Chem. 2007, 50, 6303–6306.
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A. K. P.; Ren, N.; Wilsie, L. C.; Krsmanovic, M. L.; Holt, T. G.;
Wolff, M. S.; Waters, M. G.; Hammond, M. L.; Tata, J. R.;
Colletti, S. L. Tetrahydro anthranilic acid as a surrogate for
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(9) Taggart, A. K. P.; Kero, J.; Gan, X.; Cai, T.-Q.; Cheng, K.;
Ippolito, M.; Reng, N.; Kaplan, R.; Wu, K.; Wu, T.-J.; Jin, L.;
Liaw, C.; Chen, R.; Richman, J.; Connolly, D.; Offermanns, S.;
Wright, S. D.; Waters, M. G. (D)-β-Hydroxybutyrate inhibits
adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J.
Biol. Chem. 2005, 29, 26649–26652.
(10) Carballo-Jane, E.; Gerckens, L. S.; Luell, S.; Parlapiano, A. S.;
Wolff, M.; Colletti, S. L.; Tata, J. R.; Taggart, A. K.; Waters, M.
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rat and dog models of vasodilation and lippolysis for the calcula-
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Toxicol. Methods 2007, 56, 308–316.
Conclusion
In conclusion, we have identified 1e, or 2-({3-[3-(5-hydro-
xypyridin-2-yl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylpropanoyl}-
amino)cyclohex-1-ene-1-carboxylic acid (MK-6892), as a
potent, selective, and full agonist for the high affinity NA
receptor GPR109A. In addition, 1e demonstrated good PK, a
remarkably clean off-target profile, and excellent ancillary
pharmacology safety. On the basis of the FFA reduction and
vasodilation studies in preclinical PD models, this compound
exhibited a significantly larger therapeutic index than NA,
suggesting a potentially useable window between lipid effects
and flushing in humans. Therefore, 1e has been selected as a
preclinical candidate for further evaluation in humans.
Experimental Section
The synthetic procedures to prepare 1b-1k are provided in the
Supporting Information.
(11) Sawahata, T.; Neal, R. A. Biotransformation of phenol to hydro-
quinone and catechol by rat liver microsomes. Mol. Pharmacol.
1983, 23, 453–460.
Supporting Information Available: Experimental procedures
for compound preparation; characterization data. This material
(12) Yin, J.; Buchwald, S. L. Pd-catalyzed intermolecular amidation of
aryl halides: the discovery that xantphos can be trans-chelating in a
palladium complex. J. Am. Chem. Soc. 2002, 124, 6043–6048.
(13) In vitro assays: Taggart, A. K.; Kero, J.; Gan, X.; Cai, T. Q.;
Cheng, K.; Ippolito, M.; Ren, N.; Kaplan, R.; Wu, K.; Wu, T. J.;
Jin, L.; Liaw, C.; Chen, R.; Richman, J.; Connolly, D. T.; Offermanns,
S.; Wright, S. D.; Waters, M. G. (D)-Beta-hydroxybutyrate inhibits
adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol.
Chem. 2005, 280, 26649–26652.
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