The Mas agonist AVE0991[1] is active in a large number of in vivo experiments, but its pharmacokinetic profile has not been reported. In the light of recent publications from Amgen [2] and Bayer [3] highlighting the frequent lack of reproducibility of published studies, we elected to thoroughly characterise AVE0991 prior to application in our own in vivo work. We considered the parent structure, derived from angiotensin receptor antagonists, unlikely to be the active biological ingredient in vivo given its modest potency and unattractive structural and physical properties set against the low doses required to deliver efficacy (0.5-3mg/kg/day) [4]. To this end we will present; 1) The substance of the hypothesis based on in silico predictions 2) Substantiating the likely metabolic profile through in vitro studies 3) Synthesis of putative metabolites as standards 4) In vivo experiments and subsequent discovery of a highly surprising, if not beautiful, profile These studies provide key lessons regarding i) use of tools and attitude to literature evidence ii) results that challenge our preconceptions as medicinal chemists iii) the value of a close-knit medicinal chemistry, synthetic chemistry and DMPK community. References 1) J. Org. Chem. 2003, 68, 5168-5173 & references therein 2) Prinz, F.; Schlange, T.; Asadullah, K. Nat. Rev. Drug Disc., 2011, 712 3) Begley, C.G.; Ellis, L.M. Nature, 2012, 531 4) Examples in cardio-protection using AVE0991: European Journal of Pharmacology ; 590 2008 276–280; Life Sciences 81, 2007, 916–923

Monster Mas agonist: Revealing the beauty in the beast

249th National Meeting (2015)

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