title: Rational design, synthesis, and structure-activity relationships of aryltriazoles as novel corticotropin-releasing factor-1 receptor antagonists.
abstract: Following the discovery of the very high binding affinity of 4-anilinopyrimidines against corticotropin-releasing factor receptor-1 (CRF(1)) (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 CRF(1) receptor, there were important differences between the different regio- (7 and 12) and stereoisomeric aryltriazoles where the R(1) or R(2) side chain in 7 has an asymmetric center. In terms of overall potency, aryltriazole analogues such as 7r bearing an N-(alpha-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-(alpha-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 CRF(1) 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 CRF(1) receptors with an IC(50) of 49 nM in a cAMP inhibition assay.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. rlowe@neurocrine.com
authors.forename: Richard F
authors.initials: RF
authors.lastname: Lowe
authors.forename: Jodene
authors.initials: J
authors.lastname: Nelson
authors.forename: Trunghau N
authors.initials: TN
authors.lastname: Dang
authors.forename: Paul D
authors.initials: PD
authors.lastname: Crowe
authors.forename: Anil
authors.initials: A
authors.lastname: Pahuja
authors.forename: James R
authors.initials: JR
authors.lastname: McCarthy
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Grigoriadis
authors.forename: Paul
authors.initials: P
authors.lastname: Conlon
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Thomas
authors.initials: T
authors.lastname: Szabo
authors.forename: Ta Kung
authors.initials: TK
authors.lastname: Chen
authors.forename: Haig
authors.initials: H
authors.lastname: Bozigian
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D015195:Drug Design; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000099052:CRF Receptor, Type 1
chemical_list: C499143:1-methyl-3-(N-(4-fluorophenylpentyl)-N-propyl)amino-5-(2-methoxy-4-dichlorophenyl)-1H-(1,2,4)triazole; D018019:Receptors, Corticotropin-Releasing Hormone; D014230:Triazoles; D000099052:CRF Receptor, Type 1; D000242:Cyclic AMP