Structure-based drug design (SBDD) efforts promoted the identification of potent ERK kinase inhibitors across two distinct chemical series. In the first, highly lipophilic efficient (LipE) tetrahydropyrazolopyridine (THPP) based inhibitors were realized by excising a benzyl substituent engaged in a lipophilic contact with a vicinal tyrosine. The key crystallographic design-stage observation driving the transformation was that a latent N-H functional group would engage a polar contact with an aspartate near the catalytic lysine in the ATP-competitive binding site. The impact of the transformation was characterized by a significant improvement in LipE, concomitant with elimination of an in vitro clearance liability. In the second, scaffold morphing efforts evolved a potent tetrahydro-pyrrolodiazepinone (THPD) series. While the THPD series demonstrated efficacy in a mouse model of BRAF mutant melanoma, rapid clearance limited its therapeutic potential. Mass spectrometry based metabolic identification studies indicated that metabolic oxidation of a tetrahydropyran (THP) moiety as the major contributing factor to the observed clearance. While it was determined that modification of the THP moiety provided no opportunity to mitigate clearance, a surrogate (1R,3R)-3-aminocyclopentanol proved  amenable to the task; regiospecific mono-fluorination of the aminocyclopentanol dramatically reduced in vitro clearance. In summary, this presentation will highlight successful SBDD and fluorination strategies for mitigating in vitro clearance.

Building ERK inhibitors. Mitigaing their clearance

249th National Meeting (2015)

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