Forward- and reverse-synthesis of piperazinopiperidine amide analogs: a general access to structurally diverse 4-piperazinopiperidine-based CCR5 antagonists.
Piperazinopiperidine amide analogs are among the most promising CCR5 antagonists. As an effective extension of a previously-reported methodology to synthesize such compounds, forward- and reverse-syntheses were successfully developed in which the convergent synthesis of the piperazinopiperidine nucleus, with a building block of 4-substituent-4-aminopiperidine, served as a common key step. The two-way approach affords a comprehensive access to the piperazinopiperidine templated library with variation on the pharmacophore sites. Thus, a SAR study of our synthesized piperazinopiperidine-based CCR5 antagonists was conducted with respect to the structure and configuration of the substituent on the piperazine ring. The S-configuration of the benzylic-substituent is vital for the CCR5 binding, and the bulky or aryl substituent on the 2-position in the piperazine ring is detrimental to the activity. By using the forward-synthesis approach, the best compound in the chiral piperazine-based CCR5 antagonist series, Sch-D (Vicriviroc), was conveniently synthesized in an excellent yield.
Feng
Dong-Zhi
DZ
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Song
Yan-Li
YL
Jiang
Xiao-Hua
XH
Chen
Li
L
Long
Ya-Qiu
YQ
D065100:CCR5 Receptor Antagonists; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D065100:CCR5 Receptor Antagonists; D010879:Piperazines; D010880:Piperidines