The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.

Methodology for the large‐scale, solid‐phase synthesis of nafarelin, I, an LH‐RH agonist and RS‐26306, III, and LH‐RH antagonist, is described. Nα‐Boc protected amino acids were used in the synthesis. The only side‐chain‐protected amino acids required were BocHis(Tos)‐OH and BocSer(t‐Bu)‐OH. The use of temporary protection on serine eliminates the formation of bis‐serine derivatives (II and IV), which presents a major limitation to the use of minimal protection schemes for large‐scale synthesis. Using this approach, the side‐chain protecting groups are cleaved during the synthesis, and HF deprotection in a separate step is not required.

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