BAY-6096: A Potent, Selective, and Highly Water-Soluble Adrenergic α2B Antagonist

Figures

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  Figure 1. Examples of known α2B receptor antagonists and respective potency vs α2B and selectivity factors. [a] IC50 vs human α2B receptor was measured with a recombinant CHO cell line (see the Supporting Information). [b] Selectivity factors calculated by dividing the IC50 for a given human α adrenoceptor subtype by the human α2B-IC50 (α#-IC50/α2B-IC50); see the Supporting Information for details on IC50 measurements.

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  Scheme 1. Synthesis of Pyridinium Salt 8 Reagents and conditions: (a) 4-(methylamino)pyridine, potassium iodide, DIPEA, DMF, 50 °C, 4.5 h, purification by reversed-phase HPLC with water/ACN containing formic acid, 33% yield. ACN = acetonitrile; DIPEA = N,N-diisopropylethylamine; DMF = N,N-dimethylformamide; HPLC = high-performance liquid chromatography.

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  Figure 2. Results of Ames test. See the Supporting Information for details on Ames test.

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  Figure 3. (a) Binding pose of compound 12 in a homology model of the α2B receptor. (b) Binding pose of compound 20 in a homology model of the α2B receptor. Compounds are depicted with green carbon atoms, blue nitrogen atoms, and red oxygen atoms. GLN-168, ASP-92, and PHE-388 are directly interacting with the ligand. Crucial hydrogen-bond and charge interactions are shown as dotted yellow lines. The figure has been prepared with Pymol (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC).

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  Figure 4. Impact on potency vs α2B and Ames test of amide bioisosteres and inverted amide 23. [a] IC50 vs human α2B receptor was measured with a recombinant CHO cell line (see the Supporting Information); [b] see the Supporting Information for details on Ames test. n.d. = not determined.

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  Figure 5. Comparison of imidazopyridine carboxamide and benzotriazole carboxamide. [a] IC50 vs human α2B receptor was measured with a recombinant CHO cell line (see the Supporting Information). [b] Selectivity factors were calculated by dividing the IC50 for a given human α adrenoceptor subtype by the human α2B-IC50 (α#-IC50/α2B-IC50); see the Supporting Information for details on IC50 measurements. [c] See the Supporting Information for details on Ames test. n.d. = not determined.

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  Figure 6. Dose-dependent inhibition of α2B agonist (44)-induced blood pressure increases by α2B antagonist (45). Data are mean ± S.E.M */**/***/**** = significant with p < 0.05/0.01/0.001/0.0001 vs vehicle = 0 (one-way ANOVA followed by Dunnett’s multiple comparison post hoc analysis), n = 7–9. [a] EC50 or IC50 vs human α2B receptor was measured with a recombinant CHO cell line (see the Supporting Information). [b] Selectivity factors were calculated by dividing the EC50 or IC50 for a given human α adrenoceptor subtype by the human α2B-EC50 or -IC50 (e.g. α#-EC50/α2B-EC50); see the Supporting Information for details on EC50 and IC50 measurements.

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  Scheme 2. Synthesis of BAY-6096 (24) Reagents and conditions: (a) (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), CsF, DMF, 90 °C, overnight, 54%; (b) NaOH aq. 1 M, THF, MeOH, r.t., 30 min, 95%; (c) N-(2-chloroethyl)-phthalimide, DMF, 110 °C, overnight, 63%; (d) HCl aq. conc., 100 °C, 3 d, 95%; (e) EDC*HCl, DMAP, DCM, r.t., overnight, 63%. aq. = aqueous; conc. = concentrated; DCM = dichloromethane; DMF = N,N-dimethylformamide; EDC*HCl = N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; MeOH = methanol; r.t. = room temperature; THF = tetrahydrofurane.