Rational Design, Synthesis, and Structure−Activity Relationships of Aryltriazoles as Novel Corticotropin-Releasing Factor-1 Receptor Antagonists

Following the discovery of the very high binding affinity of 4-anilinopyrimidines against corticotropin-releasing factor receptor-1 (CRF1) (e.g., 1, K i = 2 nM), a new series of triazoles bearing different groups has been synthesized and evaluated. The compounds were prepared by cyclizations of N-ac...

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Published in:	Journal of medicinal chemistry Vol. 48; no. 5; pp. 1540 - 1549
Main Authors:	Lowe, Richard F, Nelson, Jodene, Dang, Trunghau N, Crowe, Paul D, Pahuja, Anil, McCarthy, James R, Grigoriadis, Dimitri E, Conlon, Paul, Saunders, John, Chen, Chen, Szabo, Thomas, Chen, Ta Kung, Bozigian, Haig
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 10-03-2005
Subjects:	Animals Biological and medical sciences Blood-Brain Barrier - metabolism Cell Line Cyclic AMP - biosynthesis Drug Design Fibroblasts - metabolism Humans Male Medical sciences Mice Miscellaneous Models, Molecular Molecular Conformation Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Radioligand Assay Rats Rats, Sprague-Dawley Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors Stereoisomerism Structure-Activity Relationship Triazoles - chemical synthesis Triazoles - pharmacokinetics Triazoles - pharmacology Intravenous administration Rat CRF1 receptor Rodentia Oral administration In vitro In vivo Vertebrata Mammalia Structure activity relation Chlorine Organic compounds Animal Triazole derivatives Fluorine Organic compounds Antagonist Pharmacokinetics Chemical synthesis
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Summary:	Following the discovery of the very high binding affinity of 4-anilinopyrimidines against corticotropin-releasing factor receptor-1 (CRF1) (e.g., 1, K i = 2 nM), a new series of triazoles bearing different groups has been synthesized and evaluated. The compounds were prepared by cyclizations of N-acyl-S-methylisothioureas with alkylhydrazines or by cyclizations with hydrazine followed by alkylation. While members of this series showed potent binding affinity against CRF1 receptor, there were important differences between the different regio- (7 and 12) and stereoisomeric aryltriazoles where the R or R side chain in 7 has an asymmetric center. In terms of overall potency, aryltriazole analogues such as 7r bearing an N-(α-branched benzyl)-N-propylamino side chain were the most potent, followed by analogues such as 7a, with an N-bis(cyclopropyl)methyl-N-propylamino side chain, and analogues such as 7m, with an N-(α-branched aliphatic)-N-propylamino side chain. While the N-propyl group was crucial for high potency, we hypothesized that the terminal methyl mimicked the 5-methyl of pyrazolo[1,5-a]pyrimidines 3 and 4. Correlation of the low-energy conformers of compounds of type 3 and 7 generated by computational analyses was very good. The size and shape of the N-alkyl group dramatically changed the potency of the triazoles, which is in contrast to the SAR seen for bicyclic CRF1 antagonists. In general, the S-enantiomer was much more potent than the corresponding R-isomer. Furthermore, to a limited extent in the aryltriazole series the substituent on the 5-phenyl ring changed the potency up to 9-fold. (S)-1-Methyl-3-[N-(4-fluorophenylpentyl)-N-propyl]amino-5-(2-methoxy-4-dichlorophenyl)-1H-[1,2,4]triazole [(S)-7r] showed very potent binding affinity (K i = 2.7 nM) to CRF1 receptors with an IC50 of 49 nM in a cAMP inhibition assay.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm049339c