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 R Ayala, William C. Eckelman, Carlo Contoreggi, Kenner C. Rice

Research output: Contribution to journalArticle

35 Citations (Scopus)

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

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Bearings (structural)
Hydrophilicity
Hydrophobic and Hydrophilic Interactions
Hydroxyl Radical
Amines
pyrrolopyrimidine
CRF receptor type 1
Ethanol
Alcohols
Ligands
antalarmin

ASJC Scopus subject areas

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

Cite this

CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists. / Hsin, Ling Wei; Tian, Xinrong; Webster, Elizabeth L.; Coop, Andrew; Caldwell, Timothy M.; Jacobson, Arthur E.; Chrousos, George P.; Gold, Philip W.; Habib, Kamal E.; Ayala, Alejandro R; Eckelman, William C.; Contoreggi, Carlo; Rice, Kenner C.

In: Bioorganic and Medicinal Chemistry, Vol. 10, No. 1, 01.01.2002, p. 175-183.

Research output: Contribution to journalArticle

Hsin, LW, Tian, X, Webster, EL, Coop, A, Caldwell, TM, Jacobson, AE, Chrousos, GP, Gold, PW, Habib, KE, Ayala, AR, Eckelman, WC, Contoreggi, C & Rice, KC 2002, 'CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists', Bioorganic and Medicinal Chemistry, vol. 10, no. 1, pp. 175-183. https://doi.org/10.1016/S0968-0896(01)00261-9
Hsin, Ling Wei ; Tian, Xinrong ; Webster, Elizabeth L. ; Coop, Andrew ; Caldwell, Timothy M. ; Jacobson, Arthur E. ; Chrousos, George P. ; Gold, Philip W. ; Habib, Kamal E. ; Ayala, Alejandro R ; Eckelman, William C. ; Contoreggi, Carlo ; Rice, Kenner C. / CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists. In: Bioorganic and Medicinal Chemistry. 2002 ; Vol. 10, No. 1. pp. 175-183.
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AU - Caldwell, Timothy M.

AU - Jacobson, Arthur E.

AU - Chrousos, George P.

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