Starting from a novel 6,5-heterocyclic indazole- G-894  which was capable of interacting with Ser212 in a bidentate manner to give exquisite potency, further structural diversity and improved properties were obtained  by a core change to the imidazo[1,5-a]pyridine  GDC-0623,  a second novel 6,5-heterocyclic MEKi. Imidazo  [1,5-a]pyridine  GDC-0623  taught us that a 6,5 heterocycle  could engage  Ser212 in a monodentate interaction  and  retain cell proliferation potency. However, that slight loss in potency was offset by gains in solubility and PK versus G-894.  The 6,5-imidazo [1,5-a]-pyridine scaffold  was further optimized by incorporating  a nitrogen at the 7 position to give the 6,5-heterocyclic imidazo [1,5-a]pyrazine. The introduction of the C7 nitrogen was driven by blocking the 7 and C8 positions from metabolism  for improved metabolic stability (and PK). It was found that introduction of a nitrogen at C7 was not sufficient to result in an imidazo[1,5-a]pyrazine  analog  that improved upon GDC-0623 . However, increasing the polarity by combining a C7 nitrogen with a diol hydroxamate gave  imidazo[1,5-a]pyrazine  G-479  , which was improved over GDC-0623  in many aspects .

Identification of novel imidazo [1,5-<i>a</i>]pyrazine-6-carboxamide-containing mitogen-activated protein kinase kinase (MEK) inhibitors which exhibit a monodentate interaction with Ser212

247th National Meeting (2014)

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Identification of novel imidazo [1,5-a]pyrazine-6-carboxamide-containing mitogen-activated protein kinase kinase (MEK) inhibitors which exhibit a monodentate interaction with Ser212