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 language | English |
|---|---|
| Pages (from-to) | 175-183 |
| Number of pages | 9 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2002 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists
AU - Hsin, Ling Wei
AU - Tian, Xinrong
AU - Webster, Elizabeth L.
AU - Coop, Andrew
AU - Caldwell, Timothy M.
AU - Jacobson, Arthur E.
AU - Chrousos, George P.
AU - Gold, Philip W.
AU - Habib, Kamal E.
AU - Ayala, Alejandro R
AU - Eckelman, William C.
AU - Contoreggi, Carlo
AU - Rice, Kenner C.
PY - 2002/1/1
Y1 - 2002/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0036006471&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036006471&partnerID=8YFLogxK
U2 - 10.1016/S0968-0896(01)00261-9
DO - 10.1016/S0968-0896(01)00261-9
M3 - Article
C2 - 11738619
AN - SCOPUS:0036006471
VL - 10
SP - 175
EP - 183
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 1
ER -