C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors. Issue 8 (15th April 2016)

• Record Type: Journal Article
• Authors: Liu, Zheng; Swidorski, Jacob J.; Nowicka-Sans, Beata; Terry, Brian; Protack, Tricia; Lin, Zeyu; Samanta, Himadri; Zhang, Sharon; Li, Zhufang; Parker, Dawn D.; Rahematpura, Sandhya; Jenkins, Susan; Beno, Brett R.; Krystal, Mark; Meanwell, Nicholas A.; Dicker, Ira B.; Regueiro-Ren, Alicia
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 8(2016)
• Page Start: 1757
• Page End: 1770
• Publication Date: 2016-04-15
• Subjects: AUC area under the curve -- BA betulinic acid -- BVM bevirimat -- CA capsid -- calcd calculated -- cART combination antiretroviral therapy -- CL clearance -- Cmax the maximum concentration of a drug in the body after dosing -- CMP counts per minute -- CV confidence value -- DCM methylene chloride -- DMAP dimethylaminopyridine -- DME 1, 2-dimethoxyethane -- DMF dimethylformamide -- DMSOmix or DMSO-D6_CDCl3 dimethyl sulfoxide-d6 mix or dimethyl sulfoxide-d6_chloroform-d -- EA elemental analysis -- ELSD evaporative light scattering detector -- EtOAc ethyl acetate -- F oral bioavailability -- FBS fetal bovine serum -- FC fold change -- HPLC high performance liquid chromatography -- HSA human serum albumin -- IV intravenous -- LC liquid chromatography -- KHMDS potassium bis(trimethylsilyl)amide -- MA matrix -- MI maturation inhibitor -- MeOH methanol -- MOA mechanism of action -- MS mass spectrometry -- NADPH dihydronicotinamide-adenine dinucleotide phosphate -- NC nucleocapsid -- NFV nelfinavir -- PCC pyridinium chlorochromate -- Pd(Ph3P)4 tetrakis(triphenylphosphine)palladium(0) -- PEG polyethyleneglycol -- PK pharmacokinetic -- PO per os, oral -- RP reverse phase -- SD standard deviation -- SP spacer peptide -- TFA trifluoroacetic acid -- THF tetrahydrofuran -- TLC thin layer chromatography -- VLP viral-like particle -- Vss volume of distribution -- wt wild-type; HIV-1 -- Maturation inhibitors -- Betulinic acid -- Triterpene -- Antiviral; 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.2016.03.001
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3′3′-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound9a exhibits comparable cell culture potency toward wt virus as1 (WT EC50 = 16 nM for9a compared to 10 nM for1 ). However, the potency of9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to1 . Hence9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI.