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
Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
J Med Chem. 2005 Mar 10;48(5):1540-9. doi: 10.1021/jm049339c.
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.
在发现4-苯胺基嘧啶对促肾上腺皮质激素释放因子受体-1（CRF(1)）具有非常高的结合亲和力（例如，化合物1，K(i)=2 nM）之后，合成并评估了一系列带有不同基团的新型三唑类化合物。这些化合物通过N-酰基-S-甲基异硫脲与烷基肼环化或先与肼环化再烷基化来制备。虽然该系列成员对CRF(1)受体显示出强效的结合亲和力，但在不同区域异构体（7位和12位）以及立体异构的芳基三唑之间存在重要差异，其中7位的R(1)或R(2)侧链具有不对称中心。就整体效力而言，带有N-(α-支链苄基)-N-丙基氨基侧链的芳基三唑类似物如7r效力最强，其次是带有N-双(环丙基)甲基-N-丙基氨基侧链的类似物如7a以及带有N-(α-支链脂肪族)-N-丙基氨基侧链的类似物如7m。虽然N-丙基基团对高效力至关重要，但我们推测末端甲基模拟了吡唑并[1,5-a]嘧啶3和4的5-甲基。通过计算分析生成的3型和7型化合物的低能量构象之间的相关性非常好。N-烷基的大小和形状极大地改变了三唑类化合物的效力，这与双环CRF(1)拮抗剂的构效关系不同。一般来说，S-对映体比相应的R-异构体效力要强得多。此外，在芳基三唑系列中，5-苯环上的取代基在有限程度上使效力变化高达9倍。(S)-1-甲基-3-[N-(4-氟苯基戊基)-N-丙基]氨基-5-(2-甲氧基-4-二氯苯基)-1H-[1,2,4]三唑[(S)-7r]在cAMP抑制试验中对CRF(1)受体显示出非常强效的结合亲和力（K(i)=2.7 nM），IC(50)为49 nM。
