Pyrrolidine-5,5-trans-lactams. 2. The use of X-ray crystal structure data in the optimization of P3 and P4 substituents

Abstract

[reaction: see text] In this, the second of two letters, we describe the elaboration of the pyrrolidine-5,5-trans-lactam template to delineate the requirements for optimal substitution of the pyrrolidine and lactam nitrogen atoms. Central to the strategy is the use of rapid iterative synthesis in conjunction with X-ray crystal structure determination of ligand-protein complexes.