An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4.

Abstract:

:Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R1 side-group as phenyl or naphthalene and R2 as indole or naphthalene in different stereo configuration showed that (i) analogues with the R2-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R2-phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit the ability to optimize protein-ligand interactions; (iii) the relationship between the R1/R2 configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC50 of 0.055-0.085 μM vs. 0.130 μM, respectively).

journal_name

Bioorg Med Chem

authors

Samuels ER,Sevrioukova IF

doi

10.1016/j.bmc.2020.115349

subject

Has Abstract

pub_date

2020-03-15 00:00:00

pages

115349

issue

6

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(20)30140-1

journal_volume

28

pub_type

杂志文章
  • Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.

    abstract::G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets fo...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2020.115546

    authors: Paciaroni NG,Norwood VM 4th,Ratnayake R,Luesch H,Huigens RW 3rd

    更新日期:2020-07-15 00:00:00

  • Antibacterial activity of indolyl-quinolinium derivatives and study their mode of action.

    abstract::Filamenting temperature-sensitive mutant Z (FtsZ) is recognized as a promising target for new antibiotics development because of its high conservatism and pivotal role in the bacteria cell division. The aromatic heterocyclic scaffold of indole is known showing merit medical functions in antiviral and antimicrobial. In...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2019.02.024

    authors: Cai S,Yuan W,Li Y,Huang X,Guo Q,Tang Z,Fang Z,Lin H,Wong WL,Wong KY,Lu YJ,Sun N

    更新日期:2019-04-01 00:00:00

  • 8-Azapurines as new inhibitors of cyclin-dependent kinases.

    abstract::Purine inhibitors of cyclin-dependent kinases (CDK) seem to be a potential anticancer drug candidate as one of the first representatives, roscovitine, is passing Phase II clinical trials for cancer and glomerulonephritis. In this article, we describe a novel modification of the purine scaffold influencing CDK2 inhibit...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2005.06.007

    authors: Havlicek L,Fuksova K,Krystof V,Orsag M,Vojtesek B,Strnad M

    更新日期:2005-09-15 00:00:00

  • Structure-activity relationship at alpha-adrenergic receptors within a series of imidazoline analogues of cirazoline.

    abstract::Several analogues of cirazoline (2), a selective alpha1-adrenoreceptor agonist, were prepared and their pharmacological profiles studied. Although at the alpha1-adrenoreceptor all the compounds displayed a significant agonist activity, at the alpha2-adrenoreceptor they showed either agonist or antagonist activity depe...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/s0968-0896(00)00030-4

    authors: Pigini M,Quaglia W,Gentili F,Marucci G,Cantalamessa F,Franchini S,Sorbi C,Brasili L

    更新日期:2000-05-01 00:00:00

  • Inhibitory activity of Brazilian green propolis components and their derivatives on the release of cys-leukotrienes.

    abstract::The effects of Brazilian green propolis ethanol extract on Cry j1-induced cys-leukotrienes and histamine release from peripheral leukocytes of patients with allergic rhinitis were investigated. One of the key mechanisms for the anti-allergic properties of the extract was revealed to be the suppression of cys-LTs relea...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2009.11.007

    authors: Tani H,Hasumi K,Tatefuji T,Hashimoto K,Koshino H,Takahashi S

    更新日期:2010-01-01 00:00:00

  • Bicyclic[4.1.0]heptanes as phenyl replacements for melanin concentrating hormone receptor antagonists.

    abstract::Melanin concentrating hormone (MCH) receptor antagonists have been proposed as potential treatments of obesity. MCH receptor antagonists with a biphenylamine subunit have been reported previously at Schering-Plough. Herein, we report the discovery of bicyclo[4.1.0]heptanes as replacements for the middle phenyl ring of...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2005.12.046

    authors: Xu R,Li S,Paruchova J,McBriar MD,Guzik H,Palani A,Clader JW,Cox K,Greenlee WJ,Hawes BE,Kowalski TJ,O'Neill K,Spar BD,Weig B,Weston DJ

    更新日期:2006-05-15 00:00:00

  • Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors.

    abstract::In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsoma...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2020.115815

    authors: Degorce SL,Aagaard A,Anjum R,Cumming IA,Diène CR,Fallan C,Johnson T,Leuchowius KJ,Orton AL,Pearson S,Robb GR,Rosen A,Scarfe GB,Scott JS,Smith JM,Steward OR,Terstiege I,Tucker MJ,Turner P,Wilkinson SD,Wrigley GL,

    更新日期:2020-12-01 00:00:00

  • N-thiolated beta-lactams: Studies on the mode of action and identification of a primary cellular target in Staphylococcus aureus.

    abstract::This study focuses on the mechanism of action of N-alkylthio beta-lactams, a new family of antibacterial compounds that show promising activity against Staphylococcus and Bacillus microbes. Previous investigations have determined that these compounds are highly selective towards these bacteria, and possess completely ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2006.12.027

    authors: Revell KD,Heldreth B,Long TE,Jang S,Turos E

    更新日期:2007-03-15 00:00:00

  • Synthesis and bioactive evaluation of novel hybrids of metronidazole and berberine as new type of antimicrobial agents and their transportation behavior by human serum albumin.

    abstract::A series of novel hybrids of metronidazole and berberine as new type of antimicrobial agents were synthesized and characterized by (1)H NMR, (13)C NMR, IR, MS and HRMS spectra. Bioactive assay manifested that most of the prepared compounds exhibited effective antibacterial and antifungal activities and some showed com...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2013.05.007

    authors: Zhang L,Chang JJ,Zhang SL,Damu GL,Geng RX,Zhou CH

    更新日期:2013-07-15 00:00:00

  • The hemA gene encoding glutamyl-tRNA reductase from the archaeon Methanobacterium thermoautotrophicum strain Marburg.

    abstract::In archaea the first general tetrapyrrole precursor 5-aminolevulinic acid (ALA) is formed via the tRNA-dependent five-carbon pathway from glutamate. We have cloned the hemA gene encoding the central enzyme of the pathway glutamyl-tRNA reductase from the methanogenic archaeon Methanobacterium thermoautotrophicum by com...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/0968-0896(96)00098-3

    authors: Hungerer C,Weiss DS,Thauer RK,Jahn D

    更新日期:1996-07-01 00:00:00

  • New substrates and inhibitors of gamma-aminobutyric acid aminotransferase containing bioisosteres of the carboxylic acid group: design, synthesis, and biological activity.

    abstract::A series of potential substrates of gamma-aminobutyric acid aminotransferase (GABA-AT) with lipophilic bioisosteres of the carboxylic acid group (2-7) were synthesized and tested. Most of the synthesized compounds showed substrate activities with GABA-AT; 1H-tetrazole-5-propanamine (6) was the best of those tested. Th...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2005.09.067

    authors: Yuan H,Silverman RB

    更新日期:2006-03-01 00:00:00

  • Synthesis and evaluation of homo-bivalent GnRHR ligands.

    abstract::G protein coupled receptors (GPCRs) are important drug targets in pharmaceutical research. Traditionally, most research efforts have been devoted towards the design of small molecule agonists and antagonists. An interesting, yet poorly investigated class of GPCR modulators comprise the bivalent ligands, in which two r...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2007.04.065

    authors: Bonger KM,van den Berg RJ,Heitman LH,IJzerman AP,Oosterom J,Timmers CM,Overkleeft HS,van der Marel GA

    更新日期:2007-07-15 00:00:00

  • The influence of hydroquinone on tyrosinase kinetics.

    abstract::In vitro studies, using combined spectrophotometry and oximetry together with hplc/ms examination of the products of tyrosinase action demonstrate that hydroquinone is not a primary substrate for the enzyme but is vicariously oxidised by a redox exchange mechanism in the presence of either catechol, L-3,4-dihydroxyphe...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2012.05.041

    authors: Stratford MR,Ramsden CA,Riley PA

    更新日期:2012-07-15 00:00:00

  • Design, synthesis, and binding of homologated truncated 4'-thioadenosine derivatives at the human A3 adenosine receptors.

    abstract::We synthesized homologated truncated 4'-thioadenosine analogues 3 in which a methylene (CH(2)) group was inserted in place of the glycosidic bond of a potent and selective A(3) adenosine receptor antagonist 2. The analogues were designed to induce maximum binding interaction in the binding site of the A(3) adenosine r...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2010.08.018

    authors: Lee HW,Kim HO,Choi WJ,Choi S,Lee JH,Park SG,Yoo L,Jacobson KA,Jeong LS

    更新日期:2010-10-01 00:00:00

  • 2-(3-Aryl-2-propenoyl)-3-methylquinoxaline-1,4-dioxides: a novel cluster of tumor-specific cytotoxins which reverse multidrug resistance.

    abstract::A series of 2-(3-aryl-2-propenoyl)-3-methylquinoxaline-1,4-dioxides 3a-l were prepared by condensation of various aryl aldehydes with 2-acetyl-3-methylquinoxaline-1,4-dioxide 2. These compounds inhibit the growth of human Molt 4/C8 and CEM T-lymphocytes and the IC(50) values are mainly in the 5-30 microM range. The qu...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2009.04.021

    authors: Das U,Pati HN,Panda AK,De Clercq E,Balzarini J,Molnár J,Baráth Z,Ocsovszki I,Kawase M,Zhou L,Sakagami H,Dimmock JR

    更新日期:2009-06-01 00:00:00

  • N-[18F]fluoroethyl-4-piperidyl acetate ([18F]FEtP4A): A PET tracer for imaging brain acetylcholinesterase in vivo.

    abstract::N-[(18)F]Fluoroethyl-4-piperidyl acetate ([(18)F]FEtP4A) was synthesized and evaluated as a PET tracer for imaging brain acetylcholinesterase (AchE) in vivo. [(18)F]FEtP4A was previously prepared by reacting 4-piperidyl acetate (P4A) with 2-[(18)F]fluoroethyl bromide ([(18)F]FEtBr) at 130 degrees C for 30 min in 37% r...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/s0968-0896(03)00177-9

    authors: Zhang MR,Furutsuka K,Maeda J,Kikuchi T,Kida T,Okauchi T,Irie T,Suzuki K

    更新日期:2003-06-12 00:00:00

  • Novel symmetrical ureas as modulators of protein arginine methyl transferases.

    abstract::Methylation of histone arginine residues is an epigenetic mark related to gene expression that is implicated in a variety of biological processes and can be reversed by small-molecule modulators of protein arginine methyltransferases (PRMTs). A series of symmetrical ureas, designed as analogues of the known PRMT1 inhi...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2013.01.017

    authors: Fontán N,García-Domínguez P,Álvarez R,de Lera ÁR

    更新日期:2013-04-01 00:00:00

  • Structure-activity relationships in platelet-activating factor. Part 14: synthesis and biological evaluation of piperazine derivatives with dual anti-PAF and anti-HIV-1 activity.

    abstract::As HIV-associated dementia prevalence has risen with the lifespan of HIV-infected individuals, there is an important need for antiretroviral and anti-inflammatory drugs targeting the central nervous system. Platelet-activating factor, a mediator of inflammation, is an HIV-induced neurotoxin secreted in the infected br...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2006.07.043

    authors: Sallem W,Serradji N,Dereuddre-Bosquet N,Dive G,Clayette P,Heymans F

    更新日期:2006-12-01 00:00:00

  • Design, synthesis and evaluation of antiproliferative activity of fluorinated betulinic acid.

    abstract::Betulinic acid (BA), a pentacyclic triterpenoid, exhibits broad spectrum antiproliferative activity, but generally with only modest potency. To improve BA's pharmacological properties, fluorine was introduced as a single atom at C-2, creating two diastereomers, or in a trifluoromethyl group at C-3. We evaluated the im...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2019.05.016

    authors: Li J,Chang LC,Hsieh KY,Hsu PL,Capuzzi SJ,Zhang YC,Li KP,Morris-Natschke SL,Goto M,Lee KH

    更新日期:2019-07-01 00:00:00

  • Preparation and biological properties of biotinylated PhTX derivatives.

    abstract::We report the synthesis of several highly functionalized biotinylated philanthotoxin (PhTX) analogues (7, 8, 10, 13-16) designed on the basis of earlier structure-activity relationship studies. Despite the extensive modifications, the binding to nicotinic acetylcholine receptor (nAChR) is in the low micromolar range a...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/s0968-0896(99)00054-1

    authors: Hashimoto M,Liu Y,Fang K,Li HY,Campiani G,Nakanishi K

    更新日期:1999-06-01 00:00:00

  • A novel thrombin binding aptamer containing a G-LNA residue.

    abstract::In this work, we report the solution structure, thermodynamic studies, and the pharmacological properties of a new modified thrombin binding aptamer (TBA) containing a G-LNA residue, namely d(5'-GGTTGGTGTGGTTGg-3'), where upper case and lower case letters represent DNA and LNA residues, respectively. NMR and CD spectr...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2007.06.008

    authors: Virno A,Randazzo A,Giancola C,Bucci M,Cirino G,Mayol L

    更新日期:2007-09-01 00:00:00

  • Inhibition of human beta-tryptase by Bowman-Birk inhibitor derived peptides: creation of a new tri-functional inhibitor.

    abstract::Bowman-Birk inhibitor proteins (BBIs), which are potent inhibitors of chymotrypsin-like proteases, do not inhibit human beta-tryptase despite this protein having a chymotrypsin-like fold. We have reported previously that, in contrast, BBI-derived peptides (whose sequences incorporate the solvent exposed reactive site ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2004.09.015

    authors: Scarpi D,McBride JD,Leatherbarrow RJ

    更新日期:2004-12-01 00:00:00

  • Engineered production of cancer targeting peptide (CTP)-containing C-1027 in Streptomyces globisporus and biological evaluation.

    abstract::Conjugation of cancer targeting peptides (CTPs) with small molecular therapeutics has emerged as a promising strategy to deliver potent (but typically nonspecific) cytotoxic agents selectively to cancer cells. Here we report the engineered production of a CTP (NGR)-containing C-1027 and evaluation of its activity agai...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2016.04.017

    authors: Li W,Li X,Huang T,Teng Q,Crnovcic I,Rader C,Shen B

    更新日期:2016-09-01 00:00:00

  • Synthesis and antioxidant activity evaluation of new 7-aryl or 7-heteroarylamino-2,3-dimethylbenzo[b]thiophenes obtained by Buchwald-Hartwig C-N cross-coupling.

    abstract::New 7-aryl or 7-heteroarylamino-2,3-dimethylbenzo[b]thiophenes were prepared by palladium-catalyzed Buchwald-Hartwig cross-coupling of 7-bromo or 7-amino-2,3-dimethylbenzo[b]thiophenes, previously prepared by us, with substituted (4-methoxy or 3,4-dimethoxy) anilines and 3-aminopyridine or with substituted (3-methoxy ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2006.11.035

    authors: Queiroz MJ,Ferreira IC,Calhelha RC,Estevinho LM

    更新日期:2007-02-15 00:00:00

  • Discovery and structure-activity relationship analysis of Staphylococcus aureus sortase A inhibitors.

    abstract::Methicillin resistant Staphylococcus aureus (MRSA) is a major health problem that has created a pressing need for new antibiotics. Compounds that inhibit the S. aureus SrtA sortase may function as potent anti-infective agents as this enzyme attaches virulence factors to the cell wall. Using high-throughput screening, ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2009.08.067

    authors: Suree N,Yi SW,Thieu W,Marohn M,Damoiseaux R,Chan A,Jung ME,Clubb RT

    更新日期:2009-10-15 00:00:00

  • Phenylimidazole derivatives as specific inhibitors of bacterial enoyl-acyl carrier protein reductase FabK.

    abstract::Bacterial enoyl-acyl carrier protein (ACP) reductases (FabI and FabK) catalyze the final step in each cycle of bacterial fatty acid biosynthesis and are attractive targets for the development of new antibacterial agents. Here, we report the development of novel FabK inhibitors with antibacterial activity against Strep...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2007.08.050

    authors: Ozawa T,Kitagawa H,Yamamoto Y,Takahata S,Iida M,Osaki Y,Yamada K

    更新日期:2007-12-01 00:00:00

  • The advantages of describing covalent inhibitor in vitro potencies by IC50 at a fixed time point. IC50 determination of covalent inhibitors provides meaningful data to medicinal chemistry for SAR optimization.

    abstract::Recent years have seen a resurgence in drug discovery efforts aimed at the identification of covalent inhibitors which has led to an explosion of literature reports in this area and most importantly new approved therapies. These reports and breakthroughs highlight the significant investments made across the industry i...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2020.115865

    authors: Thorarensen A,Balbo P,Banker ME,Czerwinski RM,Kuhn M,Maurer TS,Telliez JB,Vincent F,Wittwer AJ

    更新日期:2021-01-01 00:00:00

  • Synthesis, biological evaluation, and modeling studies of inhibitors aimed at the malarial proteases plasmepsins I and II.

    abstract::The increasing resistance of the malarial parasite to antimalarial drugs is a major contributor to the reemergence of the disease and increases the need for new drug targets. The two aspartic proteases, plasmepsins I and II, from Plasmodium falciparum have recently emerged as potential targets. In an effort to inhibit...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2005.06.048

    authors: Muthas D,Nöteberg D,Sabnis YA,Hamelink E,Vrang L,Samuelsson B,Karlén A,Hallberg A

    更新日期:2005-09-15 00:00:00

  • Carbonic anhydrase activators: kinetic and X-ray crystallographic study for the interaction of D- and L-tryptophan with the mammalian isoforms I-XIV.

    abstract::An activation study of mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms I-XIV with D- and L-tryptophan has been performed both by means of kinetic and X-ray crystallographic techniques. These compounds show a time dependent activity against isozyme CA II, with activation constants of 1.13 microM for L-Trp and 0....

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2008.08.043

    authors: Temperini C,Innocenti A,Scozzafava A,Supuran CT

    更新日期:2008-09-15 00:00:00

  • Synthesis, biological evaluation, and molecular docking of N-{3-[3-(9-methyl-9H-carbazol-3-yl)-acryloyl]-phenyl}-benzamide/amide derivatives as xanthine oxidase and tyrosinase inhibitors.

    abstract::Claisen-Schmidt condensation of 3-formyl-9-methylcarbazole with various amides of 3-aminoacetophenone afforded N-{3-[3-(9-methyl-9H-carbazol-3-yl)-acryloyl]-phenyl}-benzamide/amide derivatives. All compounds were investigated for their in vitro xanthine oxidase (XO), tyrosinase and melanin production inhibitory activi...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2012.07.001

    authors: Bandgar BP,Adsul LK,Chavan HV,Shringare SN,Korbad BL,Jalde SS,Lonikar SV,Nile SH,Shirfule AL

    更新日期:2012-09-15 00:00:00