Synthesis of analogues of the anti-megakaryocytic agent anagrelide

• Main Author: Robinson, Claire L.
• Published: University of Newcastle Upon Tyne 2009
• Subjects: 615.19
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.578274

The pharmaceutical agent anagrelide 1 is used to reduce the levels of circulating blood platelets in the treatment of myeloproliferative disorders by inhibiting the growth of megakaryocytes (the precursors of platelets). It is metabolised extensively in vivo into two major metabolites: 3-hydroxyanagrelide (or BCH24426 2) and RL603 3 (Figure i). BCH24426 2 is also active against megakaryocyte growth, whereas RL603 3 is an inactive metabolite. Both anagrelide 1 and BCH24426 2 are known to inhibit the enzyme phosphodiesterase (PDE) III, which causes positive inotropic effects. This can manifest itself as undesirable side effects, such as heart palpitations and, in severe cases, heart attacks. In addition to this unwanted PDE III inhibition, anagrelide also has a poor pharmacokinetic profile. It undergoes rapid metabolism, and as such has to be administered up to four times per day. Analogues of anagrelide that prevent or reduce metabolism to a 3-hydroxylated metabolite would likely decrease the side effects and may improve the pharmacokinetic profile of the drug by increasing the half life of the parent compound. A series of 3-mono-substitued and 3,3-di-substituted anagrelide analogues were prepared as hydrobromide salts using a well established synthetic route, starting from an amino acid ester and 2,3-dichloro-6-nitrobenzyl bromide. Substitution varied from simple alkyl chains to those containing heteroatoms such as halogens, oxygen and sulfur. A total of 13 analogues were prepared in this manner. The anagrelide analogues were tested against the two targets of anagrelide (the inhibition of megakaryocyte growth and PDE III) in order to select target compounds for further development, with a view to advancing one or more into pre-clinical and clinical testing as a replacement for anagrelide.