P38 MAP kinase inhibitors: evolution of imidazole-based and pyrido-pyrimidin-2-one lead classes

The initial disclosure of tri-substituted imidazole-based drug molecules such as 1 for inhibition of p38 MAP kinase by SmithKline Beecham (SB) sparked an effort in this area at Merck and other pharmaceutical research establishments. Although analogs in this class have shown good inhibitory properties against p38 MAP kinase, their selectivity profile were modest and left much room for improvement. Attempts to discover newer compounds with improved selectivity over the prototypical SB compound 203580 (1), led to the discovery of a new sub-class of p38 inhibitors typified by compound 18 at Merck. Although this benchmark compound was potent, highly selective and orally efficacious it was burdened with compound related adverse effects in dogs that has delayed further development. In 1999, a new class of p38 inhibitors represented by clinical candidate VX-745 (26), was disclosed by Vertex Pharmaceuticals. This compound displayed unprecedented selectivity due to its unique mode of binding to the active site in p38 MAP kinase. Inspired by the exquisite selectivity profile of VX-745 [26] a scaffold re-design was initiated at Merck which resulted in the discovery of the quinazolinone, pyrimido-pyrimidone, pyrido-pyrimidone, quinolinone and naphthyridinone based p38 inhibitors.