Overall Synthesis of GSK356278: Quick Delivery of a PDE4 Inhibitor Using a Fit-for-Purpose Approach

Abstract

The family of phosphodiesterase (PDE) enzymes hydrolyse cyclic nucleotides, cAMP and cGMP, leading to their inactivation as intracellular second messengers. Inhibition of these enzymes leads to an elevation of levels of cyclic nucleotides in the cell and prolongs their action on downstream signaling pathways. PDE4, of which there are four subtypes, is widely expressed throughout the brain but is also abundant in the periphery in inflammatory and immune cells, in the gastrointestinal tract, and in cardiac myocytes. GSK356278 1 is a potent, selective, and competitive inhibitor of PDE4 enzymes currently under investigation for the treatment of CNS disorders. The initial synthetic route developed by Medicinal Chemistry Department, used several hazardous and/or expensive reagents and harsh conditions and gave relatively low yields. By targeted process of research and development plus application of analytical techniques to identify byproduct and extensive route scouting, a novel synthetic route for 1 has been developed. This contribution reports the optimisation of the chemical synthesis of 1 to develop a large-scale process suitable for its synthesis.

1H-Pyrazolo[3,4-b]pyridines: Synthesis and Biomedical Applications

“…1 H -Pyrazolo[3,4- b ]pyridines can be obtained by using 3-aminopyrazole 6 (or its derivatives) instead of aniline. The product obtained, in the majority of the cases, is a 4-chloro substituted 1 H -pyrazolo[3,4- b ]pyridine 1 [ 79 , 80 , 81 , 82 , 83 ].…”

“…The reaction can be performed by using ethanol as solvent at reflux temperature, followed by the treatment with POCl 3 [ 79 , 82 ]. Since diethyl 2-(ethoxymethylene)malonate 11 is liquid at room temperature, it is possible to perform the reaction without any solvent, using 100–110 °C for times between 1.5 and 12 h [ 80 , 81 , 83 , 84 ]. Rimland et al performed the reaction without any solvent at 160 °C for 5 h using SOCl 2 instead of POCl 3 in the last step [ 83 ].…”

Discovery of New 1,4,6-Trisubstituted-1H-pyrazolo[3,4-b]pyridines with Anti-Tumor Efficacy in Mouse Model of Breast Cancer

“…Several pyrazolo[3,4- b ]pyridine-based derivatives that bear diverse substitutions were reported to exhibit potent antiviral [ 1 , 2 ] and antibacterial [ 3 , 4 ] properties; to inhibit important enzymes, such as phosphodiesterase-4 [ 5 ], or neutrophil elastase [ 6 ]; and to serve as ligands for A1-adenosine [ 7 ] or prostaglandin E2 receptor 1 [ 8 ]. The anti-cancer potential of this class of compounds is of particular interest as they show antiproliferative activity, apoptosis induction, and angiogenesis inhibition [ 9 , 10 , 11 ], albeit through diverse molecular targets and mechanisms of action, such as targeting tubulin polymerization [ 12 ] and protein kinase signal transduction in cancer cells [ 10 , 13 , 14 , 15 ].…”

Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study

“…4 However, to this point, no human blocking studies with PDE4 modulators have been published. GSK356278 is a potent, CNS penetrant inhibitor of cAMP hydrolytic activity 5 that binds to the high-affinity rolipram binding site (HARBS) with a pIC 50 of 8.6 and is nonselective for the PDE4A, B and D isoforms. 6 In a model of anxiety in common marmosets, the therapeutic index for GSK356278 was >10 versus <1 for rolipram, 6 which may be explained by the faster HARBS dissociation rate compared to rolipram.…”