当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery of a novel series of benzoic acid derivatives as potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. 3. Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety.

Discovery of a novel series of benzoic acid derivatives as potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. 3. Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety.

Abstract：

:We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds ( 10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC50 = 0.38 nM) for beta3, high selectivity over beta1 and beta2, and good pharmacokinetic properties in rats, dogs, and monkeys.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Imanishi M,Nakajima Y,Tomishima Y,Hamashima H,Washizuka K,Sakurai M,Matsui S,Imamura E,Ueshima K,Yamamoto T,Yamamoto N,Ishikawa H,Nakano K,Unami N,Hamada K,Matsumura Y,Takamura F,Hattori K

doi

10.1021/jm800222k

subject

Has Abstract

pub_date

2008-08-14 00:00:00

pages

4804-22

issue

15

eissn

0022-2623

issn

1520-4804

journal_volume

51

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Disabling erbB receptors with rationally designed exocyclic mimetics of antibodies: structure-function analysis.

    abstract：:Overexpression of the HER2 receptor is observed in about 30% of breast and ovarian cancers and is often associated with an unfavorable prognosis. We have recently designed an anti-HER2 peptide (AHNP) based on the structure of the CDR-H3 loop of the anti-HER2 rhumAb 4D5 and showed that this peptide can mimic some funct...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm000527m

    authors： Berezov A,Zhang HT,Greene MI,Murali R

    更新日期：2001-08-02 00:00:00

  • Investigations on the effects of basic side chains on the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines.

    abstract：:Basic side chains determine the pharmacology of selective estrogen receptor modulators such as tamoxifen or raloxifene. In this study we tried to turn the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines from agonistic to antagonistic by introduction of a dimethylaminoethane, a piperidin-1-y...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm040855c

    authors： von Rauch M,Busch S,Gust R

    更新日期：2005-01-27 00:00:00

  • Spiro[(dihydropyrazin-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)]-based cytotoxic agents: structure-activity relationship studies on the substituent at N4-position of the diketopiperazine domain.

    abstract：:Analogues of the previously reported potent cytotoxic spiro[(dihydropyrazine-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)] derivatives (3, 3') were prepared to explore new structural requirements at the diketopiperazine domain for the cytotoxic activity. The in vitro activity was evaluated against t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm7013056

    authors： Gomez-Monterrey I,Campiglia P,Carotenuto A,Stiuso P,Bertamino A,Sala M,Aquino C,Grieco P,Morello S,Pinto A,Ianelli P,Novellino E

    更新日期：2008-05-22 00:00:00

  • Synthesis and central nervous system evaluation of some 5-alkoxy-3H-1,4-benzodiazepin-2(1H)-ones.

    abstract：:A series of 1-R-5-alkoxy-3H-1,4-benzodiazepin-2(1H)-ones was prepared and evaluated for central nervous system depressant activity. Several of these compounds, in particular, 7-chloro-5-ethoxy-1-methyl-3H-1,4-benzodiazepin-2(1H)-one (2), gave a profile and activity level similar to diazepam when measured in mice. ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00217a019

    authors： Gogerty JH,Griot RG,Habeck D,Iorio LC,Houlihan WJ

    更新日期：1977-07-01 00:00:00

  • Renin inhibitors. Design and synthesis of a new class of conformationally restricted analogues of angiotensinogen.

    abstract：:Molecular modeling methods have been used to design a novel series of conformationally constrained cyclic peptide inhibitors of human renin. Three goals were defined: enhanced inhibitory potency, high specificity for renin, and increased metabolic stability. Three cyclic compounds were synthesized with ring sizes 10, ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00397a003

    authors： Sham HL,Bolis G,Stein HH,Fesik SW,Marcotte PA,Plattner JJ,Rempel CA,Greer J

    更新日期：1988-02-01 00:00:00

  • A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability.

    abstract：:Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm800052b

    authors： Rawson TE,Rüth M,Blackwood E,Burdick D,Corson L,Dotson J,Drummond J,Fields C,Georges GJ,Goller B,Halladay J,Hunsaker T,Kleinheinz T,Krell HW,Li J,Liang J,Limberg A,McNutt A,Moffat J,Phillips G,Ran Y,Safina B,U

    更新日期：2008-08-14 00:00:00

  • Nonpeptide somatostatin agonists with sst4 selectivity: synthesis and structure-activity relationships of thioureas.

    abstract：:Utilizing NNC 26-9100 (11) as a structural lead, a variety of nonpeptide derivatives of somatostatin were synthesized and evaluated for sst2 and sst4 receptor binding affinity. A novel thiourea scaffold was utilized to attach (1) a heteroaromatic nucleus to mimic the Trp8 residue, (2) a nonheteroaromatic nucleus to mi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm980118e

    authors： Liu S,Tang C,Ho B,Ankersen M,Stidsen CE,Crider AM

    更新日期：1998-11-19 00:00:00

  • PRO_LIGAND: an approach to de novo molecular design. 2. Design of novel molecules from molecular field analysis (MFA) models and pharmacophores.

    abstract：:A computational approach for molecular design, PRO_LIGAND, has been developed within the PROMETHEUS molecular design and simulation system in order to provide a unified framework for the de novo generation of diverse molecules which are either similar or complementary to a specified target. In this instance, the targe...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00049a019

    authors： Waszkowycz B,Clark DE,Frenkel D,Li J,Murray CW,Robson B,Westhead DR

    更新日期：1994-11-11 00:00:00

  • Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Synthesis and activity of functionalized glutaramides.

    abstract：:Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemist...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm060133g

    authors： Pryde DC,Maw GN,Planken S,Platts MY,Sanderson V,Corless M,Stobie A,Barber CG,Russell R,Foster L,Barker L,Wayman C,Van Der Graaf P,Stacey P,Morren D,Kohl C,Beaumont K,Coggon S,Tute M

    更新日期：2006-07-13 00:00:00

  • Discovery of dual target inhibitors against cyclooxygenases and leukotriene A4 hydrolyase.

    abstract：:Dual target inhibitors against COX-2 and LTA(4)H were designed by adding functional groups from a marketed COX-2 inhibitor, Nimesulide, to an existing LTA(4)H inhibitor 1-(2-(4-phenoxyphenoxy) ethyl) pyrrolidine. A series of phenoxyphenyl pyrrolidine compounds were synthesized and tested for their inhibition activitie...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm200063s

    authors： Chen Z,Wu Y,Liu Y,Yang S,Chen Y,Lai L

    更新日期：2011-05-26 00:00:00

  • Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor.

    abstract：:A variety of dicarboxylic acid linkers introduced between the alpha-amino group of Pro(6) and the -amino group of Lys(10) of the cyclic lactam alpha-melanocyte-stimulating hormone (alpha-MSH)-derived Pro(6)-D-Phe(7)/D-Nal(2')(7)-Arg(8)-Trp(9)-Lys(10)-NH2 pentapeptide template lead to nanomolar range and selective hMC3...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm070461w

    authors： Mayorov AV,Cai M,Palmer ES,Dedek MM,Cain JP,Van Scoy AR,Tan B,Vagner J,Trivedi D,Hruby VJ

    更新日期：2008-01-24 00:00:00

  • Structure-activity relationships of an antimicrobial peptide plantaricin s from two-peptide class IIb bacteriocins.

    abstract：:Class IIb bacteriocins are ribosomally synthesized antimicrobial peptides comprising two different peptides synergistically acting in equal amounts for optimal potency. In this study, we demonstrate for the first time potent (nanomolar) antimicrobial activity of a representative class IIb bacteriocin, plantaricin S (P...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm101540e

    authors： Soliman W,Wang L,Bhattacharjee S,Kaur K

    更新日期：2011-04-14 00:00:00

  • Nitro and amino derivatives of lucanthone as antitumor agents.

    abstract：:A group of nitro and amino derivatives of lucanthone was prepared and tested for antitumor activity. Reaction of 1-chloro-4-methyl-7-nitrothioxanthenone and N,N-diethylethylenediamine gave the 7-amino analogue (11) directly, accompanied by 7-amino-1-chloro-4-methylthioxanthenone. The antitumor activity of 11 was infer...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00345a020

    authors： Archer S,Rej R

    更新日期：1982-03-01 00:00:00

  • Cytotoxic activity of metal complexes of biogenic polyamines: polynuclear platinum(II) chelates.

    abstract：:Several polynuclear Pt(II) chelates with biogenic polyamines were synthesized and screened for their potential antiproliferative and cytotoxic activity in different human cancer cell lines. To gather information regarding the structure-activity relationships underlying their biological activity, the complexes studied ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0311238

    authors： Teixeira LJ,Seabra M,Reis E,da Cruz MT,de Lima MC,Pereira E,Miranda MA,Marques MP

    更新日期：2004-05-20 00:00:00

  • Inhibitors of Bacillus subtilis DNA polymerase III. 6-Anilinouracils and 6-(alkylamino)uracils.

    abstract：:Substituted 6-anilinouracils were found to be potent inhibitors of the replication-specific enzyme, DNA polymerase III, from Bacillus subtilis. Inhibition potency was maximized by inclusion of small alkyl groups or halogens in the meta and para positions of the phenyl ring; polar substituents decreased activity consi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00175a007

    authors： Wright GE,Brown NC

    更新日期：1980-01-01 00:00:00

  • Further structure-activity relationships study of hybrid 7-{[2-(4-phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol analogues: identification of a high-affinity D3-preferring agonist with potent in vivo activity with long duration

    abstract：:This paper describes an extended structure-activity relationships study of aminotetralin-piperazine-based hybrid molecules developed earlier for dopamine D2/D3 receptors. Various analogues as positional isomers have been developed where location of the phenolic hydroxyl group has been varied on the aromatic ring. Betw...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm070860r

    authors： Biswas S,Zhang S,Fernandez F,Ghosh B,Zhen J,Kuzhikandathil E,Reith ME,Dutta AK

    更新日期：2008-01-10 00:00:00

  • New 5-unsubstituted dihydropyridines with improved CaV1.3 selectivity as potential neuroprotective agents against ischemic injury.

    abstract：:C5-unsubstituted-C6-aryl-1,4-dihydropyridines were prepared by a CAN-catalyzed multicomponent reaction from chalcones, β-dicarbonyl compounds, and ammonium acetate. These compounds were able to block Ca(2+) entry after a depolarizing stimulus and showed an improved Cav1.3/Cav1.2 selectivity in comparison with nifedipi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm500263v

    authors： Tenti G,Parada E,León R,Egea J,Martínez-Revelles S,Briones AM,Sridharan V,López MG,Ramos MT,Menéndez JC

    更新日期：2014-05-22 00:00:00

  • Synthesis and carbonic anhydrase isoenzymes I, II, IX, and XII inhibitory effects of dimethoxybromophenol derivatives incorporating cyclopropane moieties.

    abstract：:Cyclopropylcarboxylic acids and esters and cyclopropylmethanols incorporating bromophenol moieties were investigated as inhibitors of the carbonic anhydrase enzyme (CA; EC 4.2.1.1). The cis- and trans-esters 5 and 6 were obtained from the reaction of 4-allyl-1,2-dimethoxybenzene (4) with ethyl diazoacetate, which afte...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm501573b

    authors： Boztaş M,Çetinkaya Y,Topal M,Gülçin İ,Menzek A,Şahin E,Tanc M,Supuran CT

    更新日期：2015-01-22 00:00:00

  • Design, synthesis, and biological evaluation of ellipticine-estradiol conjugates.

    abstract：:Three ellipticine-estradiol conjugates were synthesized in an effort to target the cytotoxicity of ellipticine to estrogen-receptor positive cells. The three conjugates were prepared with linker chains extending from the 17 alpha position of the estradiol to N-2 (compound 3), N-6 (compound 4), and C-9 (compound 5) pos...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9602930

    authors： Devraj R,Barrett JF,Fernandez JA,Katzenellenbogen JA,Cushman M

    更新日期：1996-08-16 00:00:00

  • Nontoxic Metal-Cyclam Complexes, a New Class of Compounds with Potency against Drug-Resistant Mycobacterium tuberculosis.

    abstract：:Tuberculosis (TB) accounted for 1.5 million deaths in 2014, and new classes of anti-TB drugs are required. We report a class of functionalized 1,8-disubstituted cyclam derivatives that display low micromolar activity against pathogenic mycobacteria. These compounds inhibit intracellular growth of Mycobacterium tubercu...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00432

    authors： Yu M,Nagalingam G,Ellis S,Martinez E,Sintchenko V,Spain M,Rutledge PJ,Todd MH,Triccas JA

    更新日期：2016-06-23 00:00:00

  • Novel HldE-K inhibitors leading to attenuated Gram negative bacterial virulence.

    abstract：:We report here the optimization of an HldE kinase inhibitor to low nanomolar potency, which resulted in the identification of the first reported compounds active on selected E. coli strains. One of the most interesting candidates, compound 86, was shown to inhibit specifically bacterial LPS heptosylation on efflux pum...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm301499r

    authors： Desroy N,Denis A,Oliveira C,Atamanyuk D,Briet S,Faivre F,LeFralliec G,Bonvin Y,Oxoby M,Escaich S,Floquet S,Drocourt E,Vongsouthi V,Durant L,Moreau F,Verhey TB,Lee TW,Junop MS,Gerusz V

    更新日期：2013-02-28 00:00:00

  • Dissection of the recognition properties of p38 MAP kinase. Determination of the binding mode of a new pyridinyl-heterocycle inhibitor family.

    abstract：:The main recognition characteristics of the ATP binding site of p38 mitogen activated protein kinase alpha (p38alpha MAPK) have been explored by a combination of modeling and bioinformatics techniques, making special emphasis in the characteristics of the site that justifies binding specificity with respect to other M...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm061073h

    authors： Soliva R,Gelpí JL,Almansa C,Virgili M,Orozco M

    更新日期：2007-01-25 00:00:00

  • Discovery of quinazolines as histamine H4 receptor inverse agonists using a scaffold hopping approach.

    abstract：:From a series of small fragments that was designed to probe the histamine H(4) receptor (H(4)R), we previously described quinoxaline-containing fragments that were grown into high affinity H(4)R ligands in a process that was guided by pharmacophore modeling. With a scaffold hopping exercise and using the same in silic...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm800876b

    authors： Smits RA,de Esch IJ,Zuiderveld OP,Broeker J,Sansuk K,Guaita E,Coruzzi G,Adami M,Haaksma E,Leurs R

    更新日期：2008-12-25 00:00:00

  • Novel selective PDE4 inhibitors. 3. In vivo antiinflammatory activity of a new series of N-substituted cis-tetra- and cis-hexahydrophthalazinones.

    abstract：:The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC(50) = 8.6-9.4). The N-cycloheptyl- a...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0110340

    authors： Van der Mey M,Boss H,Hatzelmann A,Van der Laan IJ,Sterk GJ,Timmerman H

    更新日期：2002-06-06 00:00:00

  • Rigid analogues of dopamine: synthesis and interaction of 6-exo- and 6-endo-(3',4'-dihydroxyphenyl)-2-azabicyclo[2.2.2]octanes with dopamine uptake sites and receptors.

    abstract：:Two isomeric 6-endo- and 6-exo-(3',4'-dihydroxyphenyl) derivatives (1 and 2) of 2-azabicyclo[2.2.2]octane were synthesized as semirigid analogues of dopamine (DA) to help evaluate the preferred conformation of dopamine at the uptake site of the presynaptic nerve terminal and at the DA receptor. Against the uptake of 0...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00345a004

    authors： Law SJ,Morgan JM,Masten LW,Borne RF,Arana GW,Kula NS,Baldessarini RJ

    更新日期：1982-03-01 00:00:00

  • Orally effective acid prodrugs of the beta-lactamase inhibitor sulbactam.

    abstract：:Sulbactam (1) is a beta-lactamase inhibitor with limited oral bioavailability. Lipophilic double-ester prodrug sulbactam pivoxil (2) significantly improves the oral absorption of sulbactam, as does the mutual prodrug double ester sultamicillin (3). We have found that double-ester prodrugs of sulbactam terminating in a...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00163a055

    authors： English AR,Girard D,Jasys VJ,Martingano RJ,Kellogg MS

    更新日期：1990-01-01 00:00:00

  • Stereospecific high-affinity TRPV1 antagonists: chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide analogues.

    abstract：:Previously, we reported the thiourea antagonists 2a and 2b as potent and high affinity TRPV1 antagonists. For further optimization of the lead compounds, a series of their amide and alpha-substituted amide surrogates were investigated and novel chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]p...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm701049p

    authors： Ryu H,Jin MK,Kim SY,Choi HK,Kang SU,Kang DW,Lee J,Pearce LV,Pavlyukovets VA,Morgan MA,Tran R,Toth A,Lundberg DJ,Blumberg PM

    更新日期：2008-01-10 00:00:00

  • Characterization of alpha-adrenoceptor populations. Quantitative relationships between cardiovascular effects initiated at central and peripheral alpha-adrenoceptors.

    abstract：:The agonist selectivities of central (medullary) and peripheral (vascular) alpha-adrenoceptors were compared in order to investigate a possible similarity among these two alpha-adrenoceptor populations. Linear regression equations were derived between the alpha-adrenergic potencies, mediated by these two types of alph...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00137a006

    authors： Timmermans PB,de Jonge A,van Meel JC,Slothorst-Grisdijk FP,Lam E,van Zwieten PA

    更新日期：1981-05-01 00:00:00

  • Studies of pyrrolo[1,2-alpha]benzimidazolequinone DT-diaphorase substrate activity, topoisomerase II inhibition activity, and DNA reductive alkylation.

    abstract：:The influence of structure on DT-diaphorase substrate activity, topoisomerase II inhibition activity, and DNA reductive alkylation was studied for the 6-aziridinylpyrrolo[1,2-alpha]benzimidazolequinones (PBIs) and the 6-acetamidopyrrolo[1,2-alpha]benzimidazolequinones (APBIs). The PBIs are reductively activated by DT-...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm960546p

    authors： Skibo EB,Gordon S,Bess L,Boruah R,Heileman MJ

    更新日期：1997-04-25 00:00:00

  • Toll-like receptor 7 selective synthetic oligoribonucleotide agonists: synthesis and structure-activity relationship studies.

    abstract：:We previously reported a novel class of stabilized immune-modulatory RNA (SIMRA) compounds that activates TLR8 or both TLR7 and TLR8 depending on the nucleotide composition and chemical modifications incorporated. In the present study, to identify TLR7-selective agonists, we designed and synthesized novel SIMRA compou...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm901145s

    authors： Lan T,Dai M,Wang D,Zhu FG,Kandimalla ER,Agrawal S

    更新日期：2009-11-12 00:00:00