Azaindole derivatives

Yakhontov, L. N.; Krasnokutskaya, D. M.; Akalaev, A. N.; Palant, I. N.; Vainshtein, Yu. I.

doi:10.1007/bf00476822

Cited by 2 publications

(1 citation statement)

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“…The target antagonists, as discussed below, contained the 1-phenyl-7-azaindole or 1H-pyrrolo[2,3-b]pyridine core (Table 1; hereafter referred to as pyrrolopyridines). The chemistry of pyrrolopyridines has been studied in some depth by Yakhontov 12 and was reviewed by Willette. 13 Derivatives with different substitution patterns than those described here have been reported as CNS depressants and antihypertensives.…”

Section: Methodsmentioning

confidence: 99%

Corticotropin-Releasing Hormone Receptor Antagonists: Framework Design and Synthesis Guided by Ligand Conformational Studies

et al. 1999

J. Med. Chem.

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As described in the preceding paper (Arvanitis et al. J. Med. Chem. 1999, 42), anilinopyrimidines I were identified as potent antagonists of corticotropin-releasing hormone-1 receptor (CRH1-R, also referred to as corticotropin-releasing factor, CRF1-R). Our next goal was to understand the receptor-bound conformation of the antagonists and to use this information to help guide preclinical optimization of the series and to develop new leads. Since receptor structural information was not available, we assumed that these small, high-affinity antagonists would tend to bind in conformations at or energetically close to their global minima and that rigid analogues that maintained the important stereoelectronic features of the bound anilinopyrimidine would also bind tightly. Conformational preferences and barriers to rotation of the anilinopyrimidines were determined by semiempirical methods, and X-ray and variable-temperature NMR spectroscopy provided experimental results that correlated well with calculated structures. Using these data, a key dihedral angle was constrained to design fused-ring analogues, substituted N-arylpyrrolopyridines II, synthesis of which provided CRH1 receptor antagonists with potency equal to that of the initial congeneric leads (Ki = 1 nM) and which closely matched the conformation held by the original compound, as determined by crystallography. In addition to providing a useful template for further analogue synthesis, the study unequivocally determined the active conformation of the anilinopyrimidines. Theoretical and spectroscopic studies, synthesis, and receptor binding data are presented.

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Section: Methodsmentioning

confidence: 99%