Design, Synthesis And Structure-activity Relationship Of Arylpiperazine Derivatives Of α₁-receptor Antagonists

Backgroud:α1-adrenergic receptor (α1-AR) , belong to G protein-coupled receptor ,at least divided into three subclasses(α1A,α1B,α1D) in Pharmacology, is widely distributed in a variety of organizations and is responsible for many physiological effects. In recent years, a new subtype (α1L) is recognized,but its function is need to be further studied.α1-adrenoceptor antagonists can be useful in the treatment of hypertension and benign prostatic hyperplasia (BPH). Along with the trend of the world's population aging, hypertension, the incidence of BPH and BPH combined with hypertension is increasing gradually,which makes the development ofα1-adrenergic receptor antagonist as a very active area in pharmaceutical research. Existence of multipleα1-AR subtypes holds great promise for the discovery and development of more specific selective drug molecules, targeting only oneα1-AR subtype and free from side effects.The most recent models ofα1-adrenergic receptor antagonist,elaborated using radioligand binding data and computer aided methods with catalyst have been proposed by Barbaro et al. Barbaro's model, especially useful for phenylpiperazine derivatives, has postulated five pharmacophore features: a positive ionisable atom(PI), three hydrophobic regions (HY1–HY3), and a hydrogen bond acceptor (HBA).Arylpiperazine derivatives (such as NAF, researched and developmented by our group) is a very important class ofα1-adrenoceptor antagonists. Nearly 200 derivatives were designed and synthesized based on Naftopidil and its active metabolites as the lead compounds by our group. In this paper, 74 derivatives were chosen for in vitro screening, and analysis of their structure-activity relationship (SAR) combination of screening results including 77 arylpiperazine derivatives of compounds received by by our group. Then, a series of new compounds were designed and synthesized according to the SAR. Research contents:Part I. In vitro screening of 74 arylpiperazine derivatives of compounds synthesized by our group using arterial rings and then analysis of their structure-activity relationship (SAR) combination of screening results including 77 arylpiperazine derivatives of compounds received by our group.Part II: According to the SAR discovered by Part I and Barbaro's model, design and synthesis 10 new compounds(JL01~JL10) based on NAF and its active metabolites as the lead compounds.Then, preliminarily confirm their structure by 1HNMR, ESI -MS and IR.Part III: In vitro screening of 10 target compounds using arterial rings. Verify and supplement the structure-activity relationship of arylpiperazine derivatives ofα1-adrenergic receptor antagonist.Research results:The SAR obtained thereof are as follows:1. Ortho-substituted (such as methoxy, ethoxy, chlorine)arylpiperazine has the best activity and among them, the best is 2-alkoxyphenylpiperazine:2-methoxyphenyl or 2-ethoxyphenyl.2. Neither meta- or para- position is not suitable to be replaced. Compared to electron-withdrawing groups(such as methoxy, ethoxy, chlorine, fluoride and so on), electron-donating group such as methy is little detrimentally. It can be considered to use of methyl to replace on meta- or para- position, if you want to improve the pharmacokinetic properties of compounds.3. The activity is better when the the left part of aromatic heterocyclic is nitrogen-containing or oxygen-containing aromatic heterocyclic. Moreover, rigid structure is more potent than non-rigid structure.4. According to the SAR discovered by Part I and Barbaro's model, 10 new compounds(JL01~JL10) were designed and synthesized based on NAF and its active metabolites as the lead compounds.All target compounds and key intermediates were preliminarily confirmed by 1HNMR, ESI -MS and IR.5. Compound JL04 is much more active than NAF(the ratio of inhibition rate is 1.5 when the concentration of 1.0×10-6 mol/L, and the ratio of inhibition rate is 2.2 when the concentration of 1.0×10-7 mol/L); compounds JL03, JL06, JL07 have the considerable activity as NAF; compounds JL01, JL02, JL05, JL08, JL09, JL10 are active, but less potent than NAF.