Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors.


:Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.


Bioorg Med Chem Lett


Hu CH,Wang TC,Qiao JX,Haque L,Chen AYA,Taylor DS,Ying X,Onorato JM,Galella M,Shen H,Huang CS,Toussaint N,Li YX,Abell L,Adam LP,Gordon D,Wexler RR,Finlay HJ




Has Abstract


2018-12-15 00:00:00














  • Discovery of non-peptidergic MrgX1 and MrgX2 receptor agonists and exploration of an initial SAR using solid-phase synthesis.

    abstract::A class of small molecules displaying comparable activities with peptide ligands BAM22 and corticostatin-14 at both the human and rhesus monkey MrgX1 and MrgX2 receptors, respectively, was discovered. A comparative study to compare solid-phase and solution-phase chemistries for the efficient synthesis of the active cl...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Malik L,Kelly NM,Ma JN,Currier EA,Burstein ES,Olsson R

    更新日期:2009-03-15 00:00:00

  • Preparation, characterization and cytotoxic evaluation of bovine serum albumin nanoparticles encapsulating 5-methylmellein: A secondary metabolite isolated from Xylaria psidii.

    abstract::In this study, 5-methylmellein (5-MM) loaded bovine serum albumin nanoparticles (BSA NPs) were developed using desolvation technique. The developed nanoparticles were characterized for their mean particle size, polydispersity, zeta potential, loading efficiency, X-ray diffractometry (XRD), differential scanning calori...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Arora D,Kumar A,Gupta P,Chashoo G,Jaglan S

    更新日期:2017-12-01 00:00:00

  • Novel targeting strategy based on multimeric ligands for drug delivery and molecular imaging: homooligomers of alpha-MSH.

    abstract::Homooligomers constructed with 4- and 6-amino acid fragments of melanocortin (alpha-MSH) bind with higher affinity and with apparent cooperativity to melanocortin receptor, compared to their constituent monomers. Individual ligands were tethered with various spacers of different length and rigidity and the influence o...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Vagner J,Handl HL,Gillies RJ,Hruby VJ

    更新日期:2004-01-05 00:00:00

  • Discovery of dual ZAP70 and Syk kinases inhibitors by docking into a rare C-helix-out conformation of Syk.

    abstract::The non-receptor tyrosine kinase Syk (spleen tyrosine kinase) is a pharmaceutical relevant target because its over-activation is observed in several autoimmune diseases, allergy, and asthma. Here we report the identification of two novel inhibitors of Syk by high-throughput docking into a rare C-helix-out conformation...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Zhao H,Caflisch A

    更新日期:2014-03-15 00:00:00

  • 1-Aryl-tetrahydroisoquinoline analogs as active anti-HIV agents in vitro.

    abstract::A series of 1-aryl-6,7-dihydroxyl(methoxy)-1,2,3,4-tetrahydroisoquinolines (compounds 1-36) were synthesized via Pictet-Spengler cyclization. All the synthesized compounds were assayed for activities against HIV-1(IIIB) in C8166 cell cultures by MTT method for the first time. The results of the anti-HIV screening reve...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Cheng P,Huang N,Jiang ZY,Zhang Q,Zheng YT,Chen JJ,Zhang XM,Ma YB

    更新日期:2008-04-01 00:00:00

  • Synthesis and anticancer activity of side chain analogs of the crambescidin alkaloids.

    abstract::Twenty three side chain analogs of the crambescidin alkaloids were prepared from the corresponding pentacyclic zwitterionic core acid. In the crambescidin 800 and 657 series, potency increased with increasing chain length. In addition, substantial variations in tumor selectivity with structure were seen. Crambescidin ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Aron ZD,Pietraszkiewicz H,Overman LE,Valeriote F,Cuevas C

    更新日期:2004-07-05 00:00:00

  • Synthesis, antiviral activity and pharmacokinetics of P1/P1' substituted 3-aminoindazole cyclic urea HIV protease inhibitors.

    abstract::A series of P1/P1' substituted cyclic urea analogues were prepared in an attempt to increase the intra-cellular antiviral potency of the nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851. The effect of alkyl substitution of the P1/P1' residues on cellular antiviral potency, protein binding, resistance profile and ph...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kaltenbach RF 3rd,Patel M,Waltermire RE,Harris GD,Stone BR,Klabe RM,Garber S,Bacheler LT,Cordova BC,Logue K,Wright MR,Erickson-Viitanen S,Trainor GL

    更新日期:2003-02-24 00:00:00

  • Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy.

    abstract::This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50=95nM, 89% ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Gogliotti RD,Engers DW,Garcia-Barrantes PM,Panarese JD,Gentry PR,Blobaum AL,Morrison RD,Daniels JS,Thompson AD,Jones CK,Conn PJ,Niswender CM,Lindsley CW,Hopkins CR

    更新日期:2016-06-15 00:00:00

  • C29 sterols with a cyclopropane ring at C-25 and 26 from the Vietnamese marine sponge Ianthella sp. and their anticancer properties.

    abstract::Two new C(29) sterols with a cyclopropane ring at C-25 and C-26, petrosterol-3,6-dione (1) and 5alpha,6alpha-epoxy-petrosterol (2), along with petrosterol (3), were isolated from the Vietnamese marine sponge Ianthella sp. The structures of the new compounds were elucidated by comprehensive spectroscopic analyses. Comp...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Nguyen HT,Chau VM,Tran TH,Phan VK,Hoang TH,Nguyen TD,Nguyen XN,Tai BH,Hyun JH,Kang HK,Kim YH

    更新日期:2009-08-15 00:00:00

  • Polar substitutions in the benzenesulfonamide ring of celecoxib afford a potent 1,5-diarylpyrazole class of COX-2 inhibitors.

    abstract::Several chemical modifications in the N(1)-benzenesulfonamide ring of celecoxib are presented. The series with a hydroxymethyl group adjacent to the sulfonamide was found to be the most potent modification that yielded many compounds selectively active against COX-2 enzyme in vitro. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Singh SK,Reddy PG,Rao KS,Lohray BB,Misra P,Rajjak SA,Rao YK,Venkateswarlu A

    更新日期:2004-01-19 00:00:00

  • A highly atom economic, chemo-, regio- and stereoselective synthesis and evaluation of spiro-pyrrolothiazoles as antitubercular agents.

    abstract::The 1,3-dipolar cycloaddition of azomethine ylides derived from substituted isatins and 1,3-thiazolane-4-carboxylic acid to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]-tetrahydro-4(1H)-pyridinones afforded novel spiro-pyrrolothiazoles chemo-, regio- and stereoselectively in quantitative yields. These compounds w...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Karthikeyan SV,Bala BD,Raja VP,Perumal S,Yogeeswari P,Sriram D

    更新日期:2010-01-01 00:00:00

  • Thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDK1 inhibitors discovered by fragment-based screening.

    abstract::Ligand efficient fragments binding to PDK1 were identified by an NMR fragment-based screening approach. Computational modeling of the fragments bound to the active site led to the design and synthesis of a series of novel 6,7-disubstituted thienopyrimidin-4-one compounds, with low micromolar inhibitory activity agains...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lee AC,Ramanujulu PM,Poulsen A,Williams M,Blanchard S,Ma DM,Bonday Z,Goh KL,Goh KC,Goh MK,Wood J,Dymock BW

    更新日期:2012-06-15 00:00:00

  • Design and regioselective synthesis of a new generation of targeted chemotherapeutics. Part II: Folic acid conjugates of tubulysins and their hydrazides.

    abstract::Efficient syntheses of folate conjugates of tubulysins and their hydrazides 1a-d are described. These water soluble folate receptor (FR) targeted conjugates are derivatives of folic acid and the potent cytotoxic agents: tubulysin A, B, or their respective hydrazides, connected in regioselective manner via a hydrophili...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Vlahov IR,Wang Y,Kleindl PJ,Leamon CP

    更新日期:2008-08-15 00:00:00

  • Pyrrolo[2,3-h]quinolinones: synthesis and photochemotherapic activity.

    abstract::A series of derivatives of the new ring system pyrrolo[2,3-h]quinoline-2-one was synthesized and evaluated as photoreagents toward cultured human tumor cells. Remarkable phototoxycity resulted for some derivatives, especially those bearing the phenyl group at the 7-position. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Barraja P,Diana P,Lauria A,Montalbano A,Almerico AM,Dattolo G,Cirrincione G,Viola G,Dall'Acqua F

    更新日期:2003-08-18 00:00:00

  • Dual functional cholinesterase and PDE4D inhibitors for the treatment of Alzheimer's disease: Design, synthesis and evaluation of tacrine-pyrazolo[3,4-b]pyridine hybrids.

    abstract::A series of tacrine-pyrazolo[3,4-b]pyridine hybrids were synthesised and evaluated as dual cholinesterase (ChE) and phosphodiesterase 4D (PDE4D) inhibitors for the treatment of Alzheimer's disease (AD). Compound 10j, which is tacrine linked with pyrazolo[3,4-b]pyridine moiety by a six-carbon spacer, was the most poten...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 信件


    authors: Pan T,Xie S,Zhou Y,Hu J,Luo H,Li X,Huang L

    更新日期:2019-08-15 00:00:00

  • Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine.

    abstract::The naturally occurring aporphine alkaloid nantenine, has been shown to antagonize behavioral and physiological effects of MDMA in mice. We have synthesized (+/-)-nantenine via an oxidative cyclization reaction with PIFA and evaluated its binding profile against a panel of CNS targets. To begin to understand the impor...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Legendre O,Pecic S,Chaudhary S,Zimmerman SM,Fantegrossi WE,Harding WW

    更新日期:2010-01-15 00:00:00

  • Photo-controlled release of fipronil from a coumarin triggered precursor.

    abstract::Developing efficient controlled release system of insecticide can facilitate the better use of insecticide. We described here a first example of photo-controlled release of an insecticide by linking fipronil with photoresponsive coumarin covalently. The generated coumarin-fipronil (CF) precursor could undergo cleavage...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Gao Z,Yuan P,Wang D,Xu Z,Li Z,Shao X

    更新日期:2017-06-01 00:00:00

  • Recent advances in peptidomimetics antagonists targeting estrogen receptor α-coactivator interaction in cancer therapy.

    abstract::Estrogen receptor α (ERα) is a crucial target for ERα positive breast cancer treatment. Previous drug discovery efforts were focused on developing inhibitors that targeted the canonical ligand binding pockets of the ligand binding domain (LBD) of ERα. However, significant percentage of patients developed cancer relaps...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章,评审


    authors: Qin W,Xie M,Qin X,Fang Q,Yin F,Li Z

    更新日期:2018-09-15 00:00:00

  • A practical deuterium-free NMR method for the rapid determination of 1-octanol/water partition coefficients of pharmaceutical agents.

    abstract::A simple and rapid NMR method is described to determine the logP of pharmaceutical agents. This method is highly versatile and efficient, because it does not require the use of deuterated solvents or the addition of any internal/external standards to the sample. We demonstrate that logP can be accurately measured usin...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Mo H,Balko KM,Colby DA

    更新日期:2010-11-15 00:00:00

  • Orally bioavailable anti-HBV dinucleotide acyloxyalkyl prodrugs.

    abstract::The acyloxyalkyl derivatives of a model anti-HBV dinucleotide were synthesized and evaluated as orally bioavailable prodrugs. Our studies have led to the identification of the first orally bioavailable dinucleotide prodrugs for further therapeutic development against the hepatitis B virus (HBV). ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Coughlin JE,Padmanabhan S,Zhang G,Kirk CJ,Govardhan CP,Korba BE,O'Loughlin K,Green CE,Mirsalis J,Morrey JD,Iyer RP

    更新日期:2010-03-01 00:00:00

  • Targeting prostate cancer cells with a multivalent PSMA inhibitor-guided streptavidin conjugate.

    abstract::Prostate-specific membrane antigen (PSMA), a type II membrane glycoprotein, its high expression is associated with prostate cancer progression, and has been becoming an active target for imaging or therapeutic applications for prostate cancer. On the other hand, streptavidin-biotin system has been successfully employe...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Liu T,Nedrow-Byers JR,Hopkins MR,Wu LY,Lee J,Reilly PT,Berkman CE

    更新日期:2012-06-15 00:00:00

  • P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K.

    abstract::An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, s...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Barrett DG,Boncek VM,Catalano JG,Deaton DN,Hassell AM,Jurgensen CH,Long ST,McFadyen RB,Miller AB,Miller LR,Payne JA,Ray JA,Samano V,Shewchuk LM,Tavares FX,Wells-Knecht KJ,Willard DH Jr,Wright LL,Zhou HQ

    更新日期:2005-08-01 00:00:00

  • Synthesis and biological evaluation of sulfonamidooxazoles and beta-keto sulfones: selective inhibitors of 11beta-hydroxysteroid dehydrogenase type I.

    abstract::The design, synthesis, and biological evaluation of arylsulfonamidooxazoles as 11beta-HSD1 inhibitors and the serendipitous discovery of beta-keto sulfones as potent 11beta-HSD1 inhibitors are described here. These two classes of compounds are not active against 11beta-HSD2 and therefore may have significant therapeut...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Xiang J,Ipek M,Suri V,Massefski W,Pan N,Ge Y,Tam M,Xing Y,Tobin JF,Xu X,Tam S

    更新日期:2005-06-02 00:00:00

  • Discovery of novel 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives as HIF prolyl 4-hydroxylase inhibitors; SAR, synthesis and modeling evaluation.

    abstract::The design, synthesis, and capacity to inhibit HIF prolyl 4-hydroxylases (PHDs) are described for 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide analogs. These analogs revealed two kinds of novel scaffolds as PHD2 inhibitors. Synthetic routes were developed for the preparation of their analogs containing the ne...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hong YR,Kim HT,Ro S,Cho JM,Lee SH,Kim IS,Jung YH

    更新日期:2014-07-15 00:00:00

  • Synthesis of 4- and 5-arylthiazolinethiones as inhibitors of indoleamine 2,3-dioxygenase.

    abstract::Docking studies of 4-phenylthiazolinethione on human IDO1 suggest complexation of the heme iron by the exocyclic sulfur atom further reinforced by hydrophobic interactions of the phenyl ring within pocket A of the enzyme. On this basis, chemical modifications were proposed to increase inhibition activity. Synthetic ro...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Balti M,Plas A,Meinguet C,Haufroid M,Thémans Q,Efrit ML,Wouters J,Lanners S

    更新日期:2017-08-01 00:00:00

  • Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors.

    abstract::A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chen P,Norris D,Das J,Spergel SH,Wityak J,Leith L,Zhao R,Chen BC,Pitt S,Pang S,Shen DR,Zhang R,De Fex HF,Doweyko AM,McIntyre KW,Shuster DJ,Behnia K,Schieven GL,Barrish JC

    更新日期:2004-12-20 00:00:00

  • Design, synthesis and anticonvulsant activities of novel 1-(substituted/unsubstituted benzylidene)-4-(4-(6,8-dibromo-2-(methyl/phenyl)-4-oxoquinazolin-3(4H)-yl)phenyl) semicarbazide derivatives.

    abstract::Novel quinazolinone derivatives 5a-5n were designed, synthesized and screened for antiepileptic activity using MES and scPTZ seizures tests. Neurotoxicity study was performed by rotorod test. Compounds 5c, 5d, 5g, 5j and 5k were found active in the preliminary screening in MES model and/or scPTZ model. Further all the...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Saravanan G,Alagarsamy V,Prakash CR

    更新日期:2012-05-01 00:00:00

  • Effect of linker substitution on the binding of butorphan univalent and bivalent ligands to opioid receptors.

    abstract::A series of bivalent hydroxy ether butorphan ligands were prepared and their binding affinities at the opioid receptors determined. Addition of a hydroxy group to a hydrocarbon chain can potentiate binding affinity up to 27- and 86-fold at the mu and kappa opioid receptors, respectively. Two bivalent ligands with sub-...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Fulton BS,Knapp BL,Bidlack JM,Neumeyer JL

    更新日期:2010-03-01 00:00:00

  • SAR of a series of inhaled A(2A) agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data.

    abstract::COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Mantell SJ,Stephenson PT,Monaghan SM,Maw GN,Trevethick MA,Yeadon M,Walker DK,Selby MD,Batchelor DV,Rozze S,Chavaroche H,Lemaitre A,Wright KN,Whitlock L,Stuart EF,Wright PA,Macintyre F

    更新日期:2009-08-01 00:00:00

  • Synthesis and characterization of bis(mu-hydroxo)diiron(III) complex of N-(4-nitro-2-hydroxy)phenylmethyl-N-(2-pyridylethyl)-N-(2-pyridylmethyl)amine and hydroxylation reaction of alkane.

    abstract::Bis(mu-hydroxo)diiron(III) complex, [Fe2III(mu-OH)2(NE)2](NO3)2 x 3H2O (3) (N-(4-nitro-2-hydroxy)phenylmethyl-N-(2-pyridylethyl)-N-(2-pyridylmethyl)amine = HNE, where H denotes a dissociable proton of the p-nitrophenol group), has been prepared and characterized by X-ray crystallography, electronic and magnetic spectr...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kurosaki H,Yoshida H,Ito M,Koike H,Higuchi E,Goto M

    更新日期:2001-03-26 00:00:00