Discovery of a Novel, Potent Spirocyclic Series of γ-Secretase Inhibitors.


:In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-β (Aβ) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of γ-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.


J Med Chem


Zhao Z,Pissarnitski DA,Josien HB,Wu WL,Xu R,Li H,Clader JW,Burnett DA,Terracina G,Hyde L,Lee J,Song L,Zhang L,Parker EM




Has Abstract


2015-11-25 00:00:00












  • Dual-action cephalosporins: cephalosporin 3'-quinolone carbamates.

    abstract::A series of cephalosporins has been prepared in which the 3'-position was linked to the nitrogen of the antibacterial quinolone ciprofloxacin through a carbamate function. Like the ester-linked and quaternary-linked dual-action cephalosporins reported earlier, these carbamate-linked compounds exhibited a broad antibac...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Albrecht HA,Beskid G,Christenson JG,Georgopapadakou NH,Keith DD,Konzelmann FM,Pruess DL,Rossman PL,Wei CC

    更新日期:1991-09-01 00:00:00

  • Synthesis and in vitro multidrug resistance modulating activity of a series of dihydrobenzopyrans and tetrahydroquinolines.

    abstract::A series of dihydrobenzopyrans and tetrahydroquinolines was synthesized and pharmacologically tested for their ability to inhibit P-glycoprotein mediated daunomycin efflux in multidrug resistant CCRF-CEM vcr1000 cells. Several compounds exhibit activities in the range of the reference compounds verapamil and propafeno...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Hiessböck R,Wolf C,Richter E,Hitzler M,Chiba P,Kratzel M,Ecker G

    更新日期:1999-06-03 00:00:00

  • Structure-activity study of hCGRP8-37, a calcitonin gene-related peptide receptor antagonist.

    abstract::A structure-activity study was carried out to determine the importance of the N-terminal amino acids of hCGRP8-37 in binding and antagonistic activity to CGRP receptors. Therefore, fragments of hCGRP8-37 as well as analogs obtained by the replacement of residues 9-12 by L-alanine were synthesized by solid-phase peptid...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Mimeault M,Quirion R,Dumont Y,St-Pierre S,Fournier A

    更新日期:1992-06-12 00:00:00

  • Novel class of LIM-kinase 2 inhibitors for the treatment of ocular hypertension and associated glaucoma.

    abstract::The discovery of a pyrrolopyrimidine class of LIM-kinase 2 (LIMK2) inhibitors is reported. These LIMK2 inhibitors show good potency in enzymatic and cellular assays and good selectivity against ROCK. After topical dosing to the eye in a steroid induced mouse model of ocular hypertension, the compounds reduce intraocul...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Harrison BA,Whitlock NA,Voronkov MV,Almstead ZY,Gu KJ,Mabon R,Gardyan M,Hamman BD,Allen J,Gopinathan S,McKnight B,Crist M,Zhang Y,Liu Y,Courtney LF,Key B,Zhou J,Patel N,Yates PW,Liu Q,Wilson AG,Kimball SD,Cros

    更新日期:2009-11-12 00:00:00

  • Naturally occurring antimicrobial peptide OH-CATH30 selectively regulates the innate immune response to protect against sepsis.

    abstract::Sepsis, which is a systemic inflammatory response that follows a bacterial infection, has a high mortality rate and limited therapeutic options. Here we show that the antimicrobial peptide OH-CATH30, which naturally occurs in snake, selectively regulates the innate immune response to protect mice from lethal sepsis. T...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Li SA,Xiang Y,Wang YJ,Liu J,Lee WH,Zhang Y

    更新日期:2013-11-27 00:00:00

  • 3-D QSAR investigations of the inhibition of Leishmania major farnesyl pyrophosphate synthase by bisphosphonates.

    abstract::We report the activities of 62 bisphosphonates as inhibitors of the Leishmania major mevalonate/isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase. The compounds investigated exhibit activities (IC(50) values) ranging from approximately 100 nM to approximately 80 microM (corresponding to K(i) values...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Sanders JM,Gómez AO,Mao J,Meints GA,Van Brussel EM,Burzynska A,Kafarski P,González-Pacanowska D,Oldfield E

    更新日期:2003-11-20 00:00:00

  • Potent inhibitors of acyl-CoA:cholesterol acyltransferase. Structure-activity relationships of novel N-(4-oxochroman-8-yl)amides.

    abstract::Novel N-(4-oxochroman-8-yl)amide derivatives 1 were synthesized and tested for their ability to inhibit rabbit small intestinal ACAT (acyl-CoA:cholesterol acyltransferase) in vitro and to lower serum total cholesterol in cholesterol-fed rats in vivo. Among the synthesized compounds, N-(7-alkoxy-4-oxochroman-8-yl)amide...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Kataoka K,Shiota T,Takeyasu T,Mochizuki T,Taneda K,Ota M,Tanabe H,Yamaguchi H

    更新日期:1995-08-04 00:00:00

  • Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK).

    abstract::As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, in...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章,评审


    authors: Kong X,Pan P,Sun H,Xia H,Wang X,Li Y,Hou T

    更新日期:2019-12-26 00:00:00

  • Selective Phenylimidazole-Based Inhibitors of the Mycobacterium tuberculosis Proteasome.

    abstract::Proteasomes of pathogenic microbes have become attractive targets for anti-infectives. Coevolving with its human host, Mycobacterium tuberculosis (Mtb) has developed mechanisms to resist host-imposed nitrosative and oxidative stresses. Genetic deletion or pharmacological inhibition of the Mtb proteasome (Mtb20S) rende...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Zhan W,Hsu HC,Morgan T,Ouellette T,Burns-Huang K,Hara R,Wright AG,Imaeda T,Okamoto R,Sato K,Michino M,Ramjee M,Aso K,Meinke PT,Foley M,Nathan CF,Li H,Lin G

    更新日期:2019-10-24 00:00:00

  • Discovery and optimization of 2,4-diaminoquinazoline derivatives as a new class of potent dengue virus inhibitors.

    abstract::The results of a high-throughput screening assay using the DENV-2 replicon showed that the 2,4-diaminoquinazoline derivative 4a has a high dengue virus inhibitory activity (EC(50) = 0.15 μM). A series of 2,4-diaminoquinazoline derivatives based on 4a as a lead compound were synthesized and subjected to structure-antid...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Chao B,Tong XK,Tang W,Li DW,He PL,Garcia JM,Zeng LM,Gao AH,Yang L,Li J,Nan FJ,Jacobs M,Altmeyer R,Zuo JP,Hu YH

    更新日期:2012-04-12 00:00:00

  • Dihydrofuro[3,4-c]pyridinones as inhibitors of the cytolytic effects of the pore-forming glycoprotein perforin.

    abstract::Dihydrofuro[3,4-c]pyridinones are the first class of small molecules reported to inhibit the cytolytic effects of the lymphocyte toxin perforin. A lead structure was identified from a high throughput screen, and a series of analogues were designed and prepared to explore structure-activity relationships around the cor...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Lena G,Trapani JA,Sutton VR,Ciccone A,Browne KA,Smyth MJ,Denny WA,Spicer JA

    更新日期:2008-12-11 00:00:00

  • Novel quinolizidinyl derivatives as antiarrhythmic agents: 2. Further investigation.

    abstract::Fifteen quinolizidine derivatives have been tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. All compounds exhibited from moderate to high antiarrhythmic activity, and five of them (3, 4, 6, 13, and 15) were more active ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Tasso B,Budriesi R,Vazzana I,Ioan P,Micucci M,Novelli F,Tonelli M,Sparatore A,Chiarini A,Sparatore F

    更新日期:2010-06-24 00:00:00

  • Prodrug-inspired probes selective to cathepsin B over other cysteine cathepsins.

    abstract::Cathepsin B (CTB) is a cysteine protease believed to be an important therapeutic target or biomarker for several diseases including aggressive cancer, arthritis, and parasitic infections. The development of probes capable of assessing CTB activity in cell lysates, living cells, and animal models of disease are needed ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Chowdhury MA,Moya IA,Bhilocha S,McMillan CC,Vigliarolo BG,Zehbe I,Phenix CP

    更新日期:2014-07-24 00:00:00

  • Design, synthesis, and biological activities of new thieno[3,2-d] pyrimidines as selective type 4 phosphodiesterase inhibitors.

    abstract::A common pharmacophore for compounds structurally related to nitraquazone has been derived. Using this pharmacophore, new structures have been designed, synthesized, and evaluated for their inhibitory potencies against cyclic adenosine 5'-monophosphate (cAMP) specific phosphodiesterase (PDE 4). From these compounds, 4...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Crespo MI,Pagès L,Vega A,Segarra V,López M,Doménech T,Miralpeix M,Beleta J,Ryder H,Palacios JM

    更新日期:1998-10-08 00:00:00

  • Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration.

    abstract::N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure, indicating that this pathway might be useful for treating obesity and associated...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Lin H,Long JZ,Roche AM,Svensson KJ,Dou FY,Chang MR,Strutzenberg T,Ruiz C,Cameron MD,Novick SJ,Berdan CA,Louie SM,Nomura DK,Spiegelman BM,Griffin PR,Kamenecka TM

    更新日期:2018-04-12 00:00:00

  • Exploration of structure-activity relationship determinants in analogue series.

    abstract::A computational methodology is introduced to systematically organize compound analogue series according to substitution sites and identify combinations of sites that determine structure-activity relationships (SARs) and make large contributions to SAR discontinuity. These sites are prime targets for further chemical m...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Peltason L,Weskamp N,Teckentrup A,Bajorath J

    更新日期:2009-05-28 00:00:00

  • Discovery of ((4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a Clinical Prodrug of p38α MAP Kinase Inhibitor.

    abstract::In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Liu C,Lin J,Hynes J,Wu H,Wrobleski ST,Lin S,Dhar TG,Vrudhula VM,Sun JH,Chao S,Zhao R,Wang B,Chen BC,Everlof G,Gesenberg C,Zhang H,Marathe PH,McIntyre KW,Taylor TL,Gillooly K,Shuster DJ,McKinnon M,Dodd JH,Bar

    更新日期:2015-10-08 00:00:00

  • Novel arylsulfoanilide-oxindole hybrid as an anticancer agent that inhibits translation initiation.

    abstract::Structure-activity relationship studies of substituted arylsulfoanilides as antiproliferatives, which are mediated by the partial depletion of intracellular Ca(2+) stores, resulted in the identification of compounds with micromolar activity against lung cancer cells in a growth inhibition assay. Incorporating the subs...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Natarajan A,Guo Y,Harbinski F,Fan YH,Chen H,Luus L,Diercks J,Aktas H,Chorev M,Halperin JA

    更新日期:2004-10-07 00:00:00

  • Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744).

    abstract::We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activi...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Johns BA,Kawasuji T,Weatherhead JG,Taishi T,Temelkoff DP,Yoshida H,Akiyama T,Taoda Y,Murai H,Kiyama R,Fuji M,Tanimoto N,Jeffrey J,Foster SA,Yoshinaga T,Seki T,Kobayashi M,Sato A,Johnson MN,Garvey EP,Fujiwara T

    更新日期:2013-07-25 00:00:00

  • Intramolecular hydrogen bonding in medicinal chemistry.

    abstract::The formation of intramolecular hydrogen bonds has a very pronounced effect on molecular structure and properties. We study both aspects in detail with the aim of enabling a more rational use of this class of interactions in medicinal chemistry. On the basis of exhaustive searches in crystal structure databases, we de...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Kuhn B,Mohr P,Stahl M

    更新日期:2010-03-25 00:00:00

  • Cyclic nitrone free radical traps: isolation, identification, and synthesis of 3,3-dimethyl-3,4-dihydroisoquinolin-4-ol N-oxide, a metabolite with reduced side effects.

    abstract::A C-4 hydroxylated metabolite (2, 3,3-dimethyl-3,4-dihydroisoquinolin-4-ol N-oxide) of the previously described cyclic nitrone free radical trap 1 (3,3-dimethyl-3,4-dihydroisoquinoline N-oxide, a cyclic analog of phenyl-tert-butylnitrone (PBN)) was isolated, identified, and synthesized. The metabolite (2), though a le...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Thomas CE,Bernardelli P,Bowen SM,Chaney SF,Friedrich D,Janowick DA,Jones BK,Keeley FJ,Kehne JH,Ketteler B,Ohlweiler DF,Paquette LA,Robke DJ,Fevig TL

    更新日期:1996-12-06 00:00:00

  • Isolation, characterization, and biological evaluation of syn and anti diastereomers of [(99m)Tc]technetium depreotide: a somatostatin receptor binding tumor imaging agent.

    abstract::The early and later eluting [(99m)TcO]depreotide products on RP-HPLC were confirmed to be the anti and syn diastereomers, respectively, based on proton NMR and circular dichroism spectroscopy. NMR provided evidence of a folded, conformationally constrained structure for the syn diastereomer. The syn diastereomer is pr...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Cyr JE,Pearson DA,Nelson CA,Lyons BA,Zheng Y,Bartis J,He J,Cantorias MV,Howell RC,Francesconi LC

    更新日期:2007-09-06 00:00:00

  • Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible T-cell kinase inhibitors.

    abstract::Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Burch JD,Lau K,Barker JJ,Brookfield F,Chen Y,Chen Y,Eigenbrot C,Ellebrandt C,Ismaili MH,Johnson A,Kordt D,MacKinnon CH,McEwan PA,Ortwine DF,Stein DB,Wang X,Winkler D,Yuen PW,Zhang Y,Zarrin AA,Pei Z

    更新日期:2014-07-10 00:00:00

  • Design, Synthesis, and Biological Evaluation of Novel DNA Gyrase-Inhibiting Spiropyrimidinetriones as Potent Antibiotics for Treatment of Infections Caused by Multidrug-Resistant Gram-Positive Bacteria.

    abstract::Spiropyrimidinetriones are a novel class of antibacterial agents that target the bacterial type II topoisomerase via a new mode of action. Compound ETX0914 is thus far the only drug from this class that is being evaluated in clinical trials. To improve the antibacterial activity and pharmacokinetic properties of ETX09...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Shi C,Zhang Y,Wang T,Lu W,Zhang S,Guo B,Chen Q,Luo C,Zhou X,Yang Y

    更新日期:2019-03-28 00:00:00

  • Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design.

    abstract::Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of TH17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetam...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Narjes F,Xue Y,von Berg S,Malmberg J,Llinas A,Olsson RI,Jirholt J,Grindebacke H,Leffler A,Hossain N,Lepistö M,Thunberg L,Leek H,Aagaard A,McPheat J,Hansson EL,Bäck E,Tångefjord S,Chen R,Xiong Y,Hongbin G,Hansson

    更新日期:2018-09-13 00:00:00

  • Synthesis, biological evaluation, and three-dimensional quantitative structure-activity relationship study of small-molecule positive modulators of adrenomedullin.

    abstract::Adrenomedullin (AM) is a peptide hormone implicated in blood pressure regulation and in the pathophysiology of several diseases such as hypertension, cancer, diabetes, and renal disorders, becoming an interesting new target for the development of drugs. In a recent high-throughput screening study, a positive modulator...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: García MA,Martín-Santamaría S,Cacho M,de la Llave FM,Julián M,Martínez A,de Pascual-Teresa B,Ramos A

    更新日期:2005-06-16 00:00:00

  • Structure-based optimization of protein tyrosine phosphatase 1B inhibitors: from the active site to the second phosphotyrosine binding site.

    abstract::Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin receptor pathways and thus an attractive therapeutic target for diabetes and obesity. Starting with a high micromolar lead compound, structure-based optimization of novel PTP1B inhibitors by extension of the molecule from the enz...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Wilson DP,Wan ZK,Xu WX,Kirincich SJ,Follows BC,Joseph-McCarthy D,Foreman K,Moretto A,Wu J,Zhu M,Binnun E,Zhang YL,Tam M,Erbe DV,Tobin J,Xu X,Leung L,Shilling A,Tam SY,Mansour TS,Lee J

    更新日期:2007-09-20 00:00:00

  • Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase.

    abstract::A homologous series of novel nitro-catechol structures (7a-7e) were synthesized and tested as inhibitors of the enzyme catechol-O-methyltransferase (COMT). Increasing chain length was found to have significant impact on both brain penetration and duration of COMT inhibition in the rat. Of this series, compound 7b (1-(...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Learmonth DA,Vieira-Coelho MA,Benes J,Alves PC,Borges N,Freitas AP,da-Silva PS

    更新日期:2002-01-31 00:00:00

  • Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class.

    abstract::A broad screening program previously identified phenprocoumon (1) as a small molecule template for inhibition of HIV protease. Subsequent modification of this lead through iterative cycles of structure-based design led to the activity enhancements of pyrone and dihydropyrone ring systems (II and V) and amide-based sub...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Turner SR,Strohbach JW,Tommasi RA,Aristoff PA,Johnson PD,Skulnick HI,Dolak LA,Seest EP,Tomich PK,Bohanon MJ,Horng MM,Lynn JC,Chong KT,Hinshaw RR,Watenpaugh KD,Janakiraman MN,Thaisrivongs S

    更新日期:1998-08-27 00:00:00

  • 5-Aryl-1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal human progesterone receptor agonists.

    abstract::The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relation...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Zhi L,Tegley CM,Kallel EA,Marschke KB,Mais DE,Gottardis MM,Jones TK

    更新日期:1998-01-29 00:00:00