Synthesis and evaluation of (E)-2-(5-phenylpent-2-en-4-ynamido)cyclohex-1-ene-1-carboxylate derivatives as HCA2 receptor agonists. Issue 16 (15th August 2017)

• Record Type: Journal Article
• Authors: Bobileva, Olga; Ikaunieks, Martins; Duburs, Gunars; Mandrika, Ilona; Petrovska, Ramona; Klovins, Janis; Loza, Einars
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 16(2017)
• Page Start: 4314
• Page End: 4329
• Publication Date: 2017-08-15
• Subjects: LDL low-density lipoprotein -- HDL high-density lipoprotein -- cAMP 3′-5′-cyclic adenosine monophosphate -- SAR structure-activity relationship -- RLB radioligand binding -- GPCR G-protein coupled receptor -- BSA bovine serum albumin -- DCM dichloromethane -- TEA triethylamine -- DIPEA diisopropylethylamine -- TBDMS tert-butyldimethylsilyl -- Pd(dppf)Cl2 [1, 1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II); YQFUXKIFZRBFFT-UHFFFAOYSA-N -- LRWGJXOTGDGXJE-WUXMJOGZSA-N -- QYZMXCUFLXBIQN-NYYWCZLTSA-N -- PJOSEOCNEGGETI-XBXARRHUSA-N -- GTBYYRMHGRYJPX-WUXMJOGZSA-N -- QNOWSKHLFSQCLS-WUXMJOGZSA-N -- RSIXRSXTZVORGJ-XBXARRHUSA-N -- NAPQUZBIWSOOFS-NTUHNPAUSA-N -- VQCCMDSEWPNDQX-UHFFFAOYSA-N -- JRSOXQYMKPJHLL-UHFFFAOYSA-N -- NMJKTRUTPRUSCO-UHFFFAOYSA-N -- CJXRUYLKNHUDNN-UHFFFAOYSA-N -- MGVBXQPPYUJBKH-UHFFFAOYSA-N -- JJMDNSVHZBHZGM-UHFFFAOYSA-N -- SHTLFPHNBFSPOG-UHFFFAOYSA-N -- TXQSOFHYCDYPCC-UHFFFAOYSA-N -- MONVNASQEVKMMQ-UHFFFAOYSA-N -- AQWGYJFRPFICJL-UHFFFAOYSA-N -- PJNHKVJGOPOFAP-UHFFFAOYSA-N -- OXNOGHLVIWCQGC-UHFFFAOYSA-N -- LCBXCTBLTKPACW-UHFFFAOYSA-N -- KKRSBZBQNMFHRN-UHFFFAOYSA-N -- OXFZQKJMXVWWHY-UHFFFAOYSA-N; HCA2 -- Niacin receptor -- CAMP -- Radioligand binding -- Agonist -- 2-Amidocyclohex-1-ene carboxylate; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.06.028
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Novel series of compounds consisting of 2-amidocyclohex-1-ene carboxylate and phenyl parts which are connected by enyne (compounds2a –f ), but-1-yne (compounds4a –j ), and phenylethylene (compounds5a –f ) linkers as HCA2 full agonists were designed and their functional activity using cAMP assay and binding affinity using radioligand ( 3 H-niacin) binding assay were evaluated. In general, compounds of all three series exhibit similar HCA2 binding and activation profile. However, the activity is strongly dependent on the substituent at the aromatic part of the structure. Among the structures evaluated, the highest affinity and potency in all series were exhibited by compounds containing 4-hydroxy and/or 2-chloro or 2-fluoro substituents. The most active compounds in the enyne and but-1-yne series in the cAMP assay are 2-fluoro, 4-hydroxy and 2-chloro, 4-hydroxy phenyl derivatives2f, 4f, and4g showing potency similar to the previously described 4-hydroxy-biphenyl analogue5c .