Norbornyllactone-substituted xanthines as adenosine A1 receptor antagonists

doi:10.1016/j.bmc.2006.01.021

Bioorganic & Medicinal Chemistry

Volume 14, Issue 11, 1 June 2006, Pages 3654-3661

https://doi.org/10.1016/j.bmc.2006.01.021 Get rights and content

Abstract

During the search for second-generation adenosine A₁ receptor antagonist alternatives to the clinical candidate 8-(3-oxa-tricyclo[3.2.1.0^2,4]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (BG9719), we developed a series of novel xanthines substituted with norbornyl-lactones that possessed high binding affinities for adenosine A₁ receptors and in vivo activity.

Graphical abstract

Introduction

Adenosine, the ubiquitous breakdown product of ATP, modulates a variety of physiologic processes by its action on four receptor subtypes: A₁, A_2A, A_2B, and A₃.¹ The A₁ receptor has been identified as a mediator in CNS, cardiovascular, metabolic, renal, and gastro-intestinal systems.² Our attention has been focused upon the development of a selective adenosine A₁ receptor antagonist for the treatment of congestive heart failure and concomitant renal impairment. 8-(3-Oxa-tricyclo[3.2.1.0^2,4]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (aka BG9719)³ was found to facilitate diuresis and stabilize the renal function in CHF patients on top of standard therapy.⁴ These promising clinical data prompted the initiation of a back-up program. Our investigations focused on the discovery of molecules with equivalent biological activity and enhanced pharmaceutical properties including increased solubility and thermal stability to those of the lead molecule, BG9719. One approach was to synthesize a series of norbornyl-based compounds that place an oxygen atom in a position similar to that of the epoxide oxygen in BG9719, such as the norbornyl-lactone with the xanthine ring in the exo-position (Fig. 1).

Section snippets

Results

The synthesis of the xanthine derivatives started from the commercially available racemic bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (Fig. 2).⁵ Iodolactonization followed by selective reduction of the iodide via a free-radical process gave lactone 2 in 42% yield over two steps.⁶ HATU-mediated (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) coupling to diaminodialkyl uracils³ produced amides 3a–c, which after stepwise base-catalyzed cyclization to the xanthine

Discussion

The binding activity of the first member of the lactone series, compound 4a, was 18 nM with 37-fold selectivity for A₁ versus A_2A receptors. This result was somewhat surprising to us in view of the relatively low A₁ affinity of the closely related trans-substituted norbornyl xanthine 13, where the xanthine occupied the endo-position and the methylcarboxylate the exo-position. Evidently locking the carboxylate into the compact lactone ring system allowed a better fit into both the A₁ and A_2A

Conclusions

A series of norbornyl-substituted lactones were investigated as replacements for the epoxynorbornane in the clinical compound BG9719. These xanthine derivatives in which the xanthine occupies the exo position on the norbornyl ring system showed high A₁ binding affinity and selectivity over the closely related A_2A receptor (notably compounds 4d: hA₁ K_i = 6 nM; 154-fold selectivity and 7: hA₁ K_i = 20 nM; 76-fold selectivity). The lactones possessed similar if not better in vivo activity to BG9719 in

General methods

Unless otherwise stated, reactions were carried out under nitrogen in oven-dried glassware. The HPLC method used to determine purity was performed on an HP1100 system, YMC-ODS-AM C18 reversed-phase column (4.6 × 100 mm)-guard column YMC-ODS-AM S-5 120A (direct connect); 20–100% CH₃CN/H₂O gradient over 8 min, buffered with 0.1% TFA at 1.5 mL/min flow rate, detector set at dual wavelength 214 and 254 nm. Reversed-phase HPLC was also used for preparative purposes (LiChroprep C-18, 310 × 25 mm). ¹H and ¹³C

Acknowledgment

We thank Dr. John Shryock (UFla) for determining rat receptor affinities for selected compounds, Dr. Herman van Vlijmen for molecular modeling advice, and Dr Maria Pellegrini and Dr Xiaoping Hronowski for aid in structural characterization.

References and notes (16)

(a)For initial screening a solution of the antagonist (1μM) was incubated with membranes in 50mM HEPES, pH 7.4, 1mM...(b)Compounds were incubated at room temperature for 90min with radioligand (2nM 3H-CPX for A1; 0.5–1.2nM 3H-ZM241385...
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Norbornyllactone-substituted xanthines as adenosine A1 receptor antagonists

Abstract

Graphical abstract

Introduction

Section snippets

Results

Discussion

Conclusions

General methods

Acknowledgment

J. Cyclic Nucleotide Res.

Pharmacol. Rev.

J. Pharmacol. Exp. Ther.

Curr. Top. Med. Chem.

Curr. Pharm. Des.

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

Drug Dev. Res.

Norbornyllactone-substituted xanthines as adenosine A₁ receptor antagonists