Optimisation of pharmacokinetic properties in a neutral series of 11β-HSD1 inhibitors
2012
Scott, J. S. (James S.) | Gill, Adrian L. | Godfrey, L. K. | Groombridge, Sam D. | Rees, Amanda | Revill, John | Schofield, Paul | Sörme, Pernilla | Stocker, Andrew | Swales, John G. | Whittamore, Paul R.O.
11β-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11β-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution.
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