title: CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists.
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) 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 (delta-hydroxy or bis-beta-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-trimethylphenyl)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.
authors.affiliation: Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 8 Center Drive MSC 0815, Bethesda, MD 20892, USA.
authors.forename: Ling-Wei
authors.initials: LW
authors.lastname: Hsin
authors.forename: Xinrong
authors.initials: X
authors.lastname: Tian
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Webster
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Caldwell
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: Philip W
authors.initials: PW
authors.lastname: Gold
authors.forename: Kamal E
authors.initials: KE
authors.lastname: Habib
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ayala
authors.forename: William C
authors.initials: WC
authors.lastname: Eckelman
authors.forename: Carlo
authors.initials: C
authors.lastname: Contoreggi
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000818:Animals; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism*; D011758:Pyrroles / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone