CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists

Ling Wei Hsin, Xinrong Tian, Elizabeth L. Webster, Andrew Coop, Timothy M. Caldwell, Arthur E. Jacobson, George P. Chrousos, Philip W. Gold, Kamal E. Habib, Alejandro Ayala, William C. Eckelman, Carlo Contoreggi, Kenner C. Rice

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

A series of compounds related to N-butyl-N-ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine (1, antalarmin, Fig. 1) have been prepared and evaluated for their CRHR1 binding affinity as the initial step in the development of selective high affinity hydrophilic nonpeptide corticotropin-releasing hormone type 1 receptor (CRHR1) antagonists. Calculated log P (Clog P) values were used to evaluate the rank order of hydrophilicity for these analogues. Introducing oxygenated functionalities (δ-hydroxy or bis-β-ethereal) into 1 gave more hydrophilic compounds, which had good affinity for the receptor. Introducing an amino group or shortening the alkyl side chain was detrimental to CRHR1 affinity. The alcohol 4-[ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]butan-1-ol (3), bearing a terminal hydroxyl group on an N-alkyl side-chain, showed the highest CRHR1 binding affinity among these compounds (Ki=0.68 nM), and is one of the highest affinity CRHR1 ligands known. Compounds 3-5, and 8, which are likely to be less lipophilic than 1, have high CRHR1 affinity and may be valuable probes to further study the CRH system.

Original languageEnglish (US)
Pages (from-to)175-183
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Hsin, L. W., Tian, X., Webster, E. L., Coop, A., Caldwell, T. M., Jacobson, A. E., Chrousos, G. P., Gold, P. W., Habib, K. E., Ayala, A., Eckelman, W. C., Contoreggi, C., & Rice, K. C. (2002). CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists. Bioorganic and Medicinal Chemistry, 10(1), 175-183. https://doi.org/10.1016/S0968-0896(01)00261-9