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

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 (K_i=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.