Developments in the synthesis of new functionalized bisphosphonate drug candidates such as cyclic prodrugs

GRAPHICAL ABSTRACT

ABSTRACT

A new series of bisphosphonic acids bearing nitrogen containing heterocycles and carbocycles has been designed and synthesized. The most potent novel bisphosphonates were shown to have lower mineral affinity but have better inhibition of farnesyl diphosphate synthase, than most clinically used bisphosphonates. However, the high polarity and charged nature of bisphosphonates result in very low oral bioavailability, resulting in highly variable absorption, especially when administered with food. To eliminate side effects and absorption issues while maintaining the bisphosphonate pharmacological activity, a series of novel potential prodrugs-cyclic esters of bisphosphonic acids was developed where the bisphosphonic acid functionality is “masked” as a cyclic ester. A new synthesis and the steric and structural isomerism of these novel cyclic bisphosphonates are discussed. The cyclic esters of bisphosphonates demonstrated better absorption, particularly in the presence of food when dosed orally. Also, several protected bisphosphonates were hydrolytically labile in vivo, thereby releasing the tetra-acid functionality of the bisphosphonates systemically after their oral absorption.

KEYWORDS:

• Bisphosphonates
• cyclic esters of bisphosphonic acids
• prodrugs

Acknowledgments

The authors appreciate the help of Dr. James Dunford, Dr. Aimee Duan, Dr. Aaron Kwaasi, and Dr. James Triffitt, University of Oxford, Oxford, United Kingdom, as well as Gwynn Jeans and Michael Quijano, Procter & Gamble, Cincinnati, Ohio, USA.