ChemInform Abstract: AZAINDOLE DERIVATIVES PART 47, SYNTHESIS AND A PHARMACOLOGICAL STUDY OF 3‐AMINOALKYL DERIVATIVES OF AZAINDOLES

Yakhontov, L. N.; Liberman, S. S.; Krasnokutskaya, D. M.; Uritskaya, M. Ya.; Azimov, V. A.; Sokolova, M. S.; Gerchikov, L. N.

doi:10.1002/chin.197509276

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“…The chemistry of pyrrolopyridines has been studied in some depth by Yakhontov and was reviewed by Willette . Derivatives with different substitution patterns than those described here have been reported as CNS depressants and antihypertensives described a synthesis that provided entry into a substitution pattern that was ideal for our purposes (Scheme ).…”

Section: Methodsmentioning

confidence: 98%

“…13 Derivatives with different substitution patterns than those described here have been reported as CNS depressants and antihypertensives. 14 Brodrick and Wibberley 15 described a synthesis that provided entry into a substitution pattern that was ideal for our purposes (Scheme 1). The syntheses of cyanopyrrolopyridines 1, 3, 7, 9, 10, and 13 (Table 1) were carried out following the basic procedure published by these authors, with modifications described in the Experimental Section.…”

Section: Methodsmentioning

confidence: 99%

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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: 98%

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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ChemInform Abstract: AZAINDOLE DERIVATIVES PART 47, SYNTHESIS AND A PHARMACOLOGICAL STUDY OF 3‐AMINOALKYL DERIVATIVES OF AZAINDOLES

Abstract: Das Azaindol (I) wird nach Vilsme yer formyliert, die Forrnylverbindung (II) mit Nitroalkanen zum Nitrovinylazaindol (III) umgesetzt und weiter zur Aminoalkylverbindung (IV) reduziert.

Cited by 1 publication

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

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

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