Corticotropin-releasing hormone receptor antagonists: Framework design andsynthesis guided by ligand conformational studies

As described in the preceding paper (Arvanitis et al. J. Med. Chem. 1999, 4 2), anilinopyrimidines I were identified as potent antagonists of corticotr opin-releasing hormone-1 receptor (CRH1-R, also referred to as corticotropi n-releasing factor, CRF1-R). Our next goal was to understand the receptor-b ound conformation of the antagonists and to use this information to help gu ide preclinical optimization of the series and to develop new leads. Since receptor structural information was not available, we assumed that these sm all, high-affinity antagonists would tend to bind in conformations at or en ergetically close to their global minima and that rigid analogues that main tained the important stereoelectronic features of the bound anilinopyrimidi ne would also bind tightly. Conformational preferences and barriers to rota tion of the anilinopyrimidines were determined by semiempirical methods, an d X-ray and variable-temperature NMR spectroscopy provided experimental res ults that correlated well with calculated structures. Using these data, a k ey dihedral angle was constrained to design fused-ring analogues, substitut ed N-arylpyrrolopyridines II, synthesis of which provided CRH1 receptor ant agonists with potency equal to that of the initial congeneric leads (K-i = 1 nM) and which closely matched the conformation held by the original compo und, as determined by crystallography. In addition to providing a useful te mplate for further analogue synthesis, the study unequivocally determined t he active conformation of the anilinopyrimidines. Theoretical and spectrosc opic studies, synthesis, and receptor binding data are presented.