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. 2012 Feb 15;22(4):1611-4.
doi: 10.1016/j.bmcl.2011.12.125. Epub 2012 Jan 4.

Imidazopyridines as selective CYP3A4 inhibitors

Xinyi Song  1 , Xiaohai Li, Claudia H Ruiz, Yan Yin, Yangbo Feng, Theodore M Kamenecka, Michael D Cameron
Affiliations

Imidazopyridines as selective CYP3A4 inhibitors

Xinyi Song et al. Bioorg Med Chem Lett. .

Abstract

Cytochrome P450s are the major family of enzymes responsible for the oxidative metabolism of pharmaceuticals and xenobiotics. CYP3A4 and CYP3A5 have been shown to have overlapping substrate and inhibitor profiles and their inhibition has been demonstrated to be involved in numerous pharmacokinetic drug-drug interactions. Here we report the first highly selective CYP3A4 inhibitor optimized from an initial lead with ≈30-fold selectivity over CYP3A5 to yield a series of compounds with greater than 1000-fold selectivity.

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Figures

Figure 1
Figure 1
Structure of imidazopyridines.
Scheme 1
Scheme 1
(a) PMB-Cl, K2CO3, DMAC; (b) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, Pd(PPh3)4, K2CO3, THF; (c) TFA; (d) RCNO, toluene.
Scheme 2
Scheme 2
(a) LiOH, methanol, THF, rt, 2 h, 90%; (b) (i) N(H)nR, HATU, N-methylmorpholine, DMF, rt, 14 h, (n=0–2).
See this image and copyright information in PMC

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