Further studies on arylpiperazinyl alkyl pyridazinones: discovery of an exceptionally potent, orally active, antinociceptive agent in thermally induced pain.

abstract：:The synthesis and matrix metalloproteinase (MMP) inhibitory activity of a series of gamma-keto carboxylic acids are described. Among nine MMP isozymes tested, compound 1j displays selective inhibition of MMP-2, -9, and -12 with IC(50) values between 0.20 and 1.51 microuM, and in male golden Syrian hamsters, it shows p...

journal_title：Journal of medicinal chemistry

authors： Ma D,Jiang Y,Chen F,Gong LK,Ding K,Xu Y,Wang R,Ge A,Ren J,Li J,Li J,Ye Q

更新日期：2006-01-26 00:00:00

abstract：:Combretastatin A-4 (CA-4) in phosphate and serine pro-drug forms is under phase II clinical trials. With our interest of discovering CA-4 inspired new chemical entities, a novel series of 4,5-diaryl-2-aminoimidazole analogues of the compound was designed and synthesized by an efficient and diversity feasible route inv...

journal_title：Journal of medicinal chemistry

authors： Chaudhary V,Venghateri JB,Dhaked HP,Bhoyar AS,Guchhait SK,Panda D

更新日期：2016-04-14 00:00:00

abstract：:Omapatrilat was designed as a vasopeptidase inhibitor with dual activity against the zinc metallopeptidases angiotensin-1 converting enzyme (ACE) and neprilysin (NEP). ACE has two homologous catalytic domains (nACE and cACE), which exhibit different substrate specificities. Here, we report high-resolution crystal stru...

journal_title：Journal of medicinal chemistry

authors： Cozier GE,Arendse LB,Schwager SL,Sturrock ED,Acharya KR

更新日期：2018-11-21 00:00:00

abstract：:Largazole 4a and analogues with modifications at the C7 position, as well as 2,4'-bithiazole 5a, have been synthesized using an acyclic cross-metathesis of the corresponding depsipeptide structures assembled by N-C6(O) or C15(O)-N lactam formation. Similar to the parent system 4a, the series of largazole depsipeptides...

journal_title：Journal of medicinal chemistry

authors： Souto JA,Vaz E,Lepore I,Pöppler AC,Franci G,Alvarez R,Altucci L,de Lera AR

更新日期：2010-06-24 00:00:00

abstract：:A series of new peroxisome proliferator activated receptors (PPARs) chiral ligands have been designed following the accepted three-module structure comprising a polar head, linker, and hydrophobic tail. The majority of the ligands incorporate the oxazolidinone moiety as a novel polar head, and the nature of the hydrop...

journal_title：Journal of medicinal chemistry

authors： Fresno N,Macías-González M,Torres-Zaguirre A,Romero-Cuevas M,Sanz-Camacho P,Elguero J,Pavón FJ,Rodríguez de Fonseca F,Goya P,Pérez-Fernández R

更新日期：2015-08-27 00:00:00

abstract：:We have previously reported a series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist ligands to serve as potential nonaddictive opioid analgesics. These ligands have been shown to be active in vivo, do not manifest withdrawal syndromes or reward behavior in conditioned-place preference assays in ...

journal_title：Journal of medicinal chemistry

authors： Henry SP,Fernandez TJ,Anand JP,Griggs NW,Traynor JR,Mosberg HI

更新日期：2019-04-25 00:00:00

abstract：:Antagonizing the robust stimulation of food intake by neuropeptide Y represents a new potential therapeutic approach for the treatment of obesity. Earlier pharmacological studies have pointed to the Y1 and Y5 receptors as the most likely mediators of the NPY orexigenic response. In this paper, we describe a new series...

journal_title：Journal of medicinal chemistry

authors： Blum CA,Zheng X,De Lombaert S

更新日期：2004-04-22 00:00:00

abstract：:The discovery and synthesis of a new series of pyrimidines as potent sigma-1 receptor (σ1R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 receptor binding assays. The nature of the pyrimidine scaffold ...

journal_title：Journal of medicinal chemistry

authors： Lan Y,Chen Y,Cao X,Zhang J,Wang J,Xu X,Qiu Y,Zhang T,Liu X,Liu BF,Zhang G

更新日期：2014-12-26 00:00:00

abstract：:In this work, a series of water-soluble propofol prodrugs were synthesized, and their propofol release rate and pharmacodynamic characteristics were measured. We found that inserting glycolic acid as a linker between propofol and the cyclic amino acid accelerated the release of propofol from prodrugs into the plasma w...

journal_title：Journal of medicinal chemistry

authors： Liu LQ,Hong PX,Song XH,Zhou CC,Ling R,Kang Y,Qi QR,Yang J

更新日期：2020-07-23 00:00:00

abstract：:The need for drugs that lack the obtrusive and limiting side effects of the tricyclic antidepressants has prompted the search for agents with greatly enhanced selectivity for specific mechanisms believed to be essential for antidepressant efficacy. The potential role of derangements of 5-HT pathways in the etiology of...

journal_title：Journal of medicinal chemistry

authors： Welch WM,Kraska AR,Sarges R,Koe BK

更新日期：1984-11-01 00:00:00

abstract：:The coupling of two different pharmacophores, each endowed with different biological properties, afforded the hybrid compound lipocrine (7), whose biological profile was markedly improved relative to those of prototypes tacrine and lipoic acid. Lipocrine is the first compound that inhibits the catalytic activity of AC...

journal_title：Journal of medicinal chemistry

authors： Rosini M,Andrisano V,Bartolini M,Bolognesi ML,Hrelia P,Minarini A,Tarozzi A,Melchiorre C

更新日期：2005-01-27 00:00:00

abstract：:The atypical chemokine receptor 3 (ACKR3)/CXC chemokine receptor 7 (CXCR7) recognizes stromal cell-derived factor 1 (SDF-1)/CXCL12 and is involved in a number of physiological and pathological processes. Here, we investigated the SAR of the component amino acids in an ACKR3-selective ligand, FC313 [ cyclo(-d-Tyr-l-Arg...

journal_title：Journal of medicinal chemistry

authors： Sekiguchi H,Kuroyanagi T,Rhainds D,Kobayashi K,Kobayashi Y,Ohno H,Heveker N,Akaji K,Fujii N,Oishi S

更新日期：2018-04-26 00:00:00

abstract：:This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discove...

journal_title：Journal of medicinal chemistry

authors： Gilligan PJ,He L,Clarke T,Tivitmahaisoon P,Lelas S,Li YW,Heman K,Fitzgerald L,Miller K,Zhang G,Marshall A,Krause C,McElroy J,Ward K,Shen H,Wong H,Grossman S,Nemeth G,Zaczek R,Arneric SP,Hartig P,Robertson DW,T

更新日期：2009-05-14 00:00:00

abstract：:1-(3'-Diethylaminopropyl)-3-(substituted phenylmethylene)pyrrolidines were synthesized and evaluated for CQ-resistant reversal activity. In general the compounds of the series elicit better biological response than their phenylmethyl analogues. The most active compound 4b has been evaluated in vivo in detail, and the ...

journal_title：Journal of medicinal chemistry

authors： Batra S,Srivastava P,Roy K,Pandey VC,Bhaduri AP

更新日期：2000-09-07 00:00:00

abstract：:2-Amino-3-aroylthiophenes are agonist allosteric enhancers (AE) at the A(1) adenosine receptor (A(1)AR). Here we report the syntheses of three kinds of novel 2-aminothiophenes and assays of their AE activity at the human A(1)AR (hA(1)AR), namely, (1) 2-amino-4,5-diphenylthiophene-3-carboxylates, 3a-h, (2) 2-amino-3-be...

journal_title：Journal of medicinal chemistry

authors： Lütjens H,Zickgraf A,Figler H,Linden J,Olsson RA,Scammells PJ

更新日期：2003-05-08 00:00:00

abstract：:Whereas the 2-propyl- and 2-butyl-5,6-(methylenedioxy)indene calcium antagonists reversed the spasmogenic action of several agonists including PGF2alpha and acetylcholine at 5 X 10(-5) to 10(-4) M on the rat ileum, the corresponding 5,6-dimethoxy analogues exhibited spasmogenic activity at higher concentration (10(-4)...

journal_title：Journal of medicinal chemistry

authors： Witiak DT,Kakodkar SV,Brunst GE,Baldwin JR,Rahwan RG

更新日期：1978-12-01 00:00:00

abstract：:Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, se...

journal_title：Journal of medicinal chemistry

authors： Erra M,Taltavull J,Bernal FJ,Caturla JF,Carrascal M,Pagès L,Mir M,Espinosa S,Gràcia J,Domínguez M,Sabaté M,Paris S,Maldonado M,Hernández B,Bravo M,Calama E,Miralpeix M,Lehner MD,Calbet M

更新日期：2018-11-08 00:00:00

abstract：:Verrucarin A (2) was epoxidized to give the beta-9,10-epoxide 7 (major product) and alpha-9,10-epoxide 9 (minor product). The beta-epoxide 7 and its acetate 8 exhibit high in vivo antileukemic activity against P-388 mouse leukemia, whereas 2 and 9 are inactive. Epoxidation of verrucarin B (3) and roridin A (1) to thei...

journal_title：Journal of medicinal chemistry

authors： Jarvis BB,Stahly GP,Pavanasasivam G,Mazzola EP

更新日期：1980-09-01 00:00:00

abstract：:A series of new 9-N-alkyl derivatives of 9(S)-erythromycylamine has been synthesized by reductive alkylation of erythromycylamine with aliphatic aldehydes and sodium cyanoborohydride. Alternative syntheses employing hydrogenation methods have also been developed. These new 9-N-alkyl derivatives possess excellent antim...

journal_title：Journal of medicinal chemistry

authors： Kirst HA,Wind JA,Leeds JP,Willard KE,Debono M,Bonjouklian R,Greene JM,Sullivan KA,Paschal JW,Deeter JB

更新日期：1990-11-01 00:00:00

abstract：:Two novel analogues, N-[2-amino-4-ethyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (2) and N-[2-amino-4-ethyl-6-methyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (4), were designed and synthesized as potent dual inhibitors of thymidylate synthase (TS) and dihydrofolate reductase (DH...

journal_title：Journal of medicinal chemistry

authors： Gangjee A,Yu J,Kisliuk RL,Haile WH,Sobrero G,McGuire JJ

更新日期：2003-02-13 00:00:00

abstract：:Mercaptopurine (6-MP), thioguanine (6-TG), and azathioprine (AZA) are purine antimetabolites introduced as anticancer or immunosuppressive drugs decades ago. Methylated AZA, called MAZA, is among the investigational drugs. The present study compares MAZA to the widely recognized drugs AZA, 6-MP, and 6-TG with respect ...

journal_title：Journal of medicinal chemistry

authors： Hoffmann M,Chrzanowska M,Hermann T,Rychlewski J

更新日期：2005-06-30 00:00:00

abstract：:A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration o...

journal_title：Journal of medicinal chemistry

authors： Kale MG,Raichurkar A,P SH,Waterson D,McKinney D,Manjunatha MR,Kranthi U,Koushik K,Jena Lk,Shinde V,Rudrapatna S,Barde S,Humnabadkar V,Madhavapeddi P,Basavarajappa H,Ghosh A,Ramya VK,Guptha S,Sharma S,Vachaspati P,

更新日期：2013-11-14 00:00:00

abstract：:The concept of bioisosterism between benzimidazole and catechol was applied to the design and synthesis of benzimidazole analogues of norepinephrine, (R,S)-1-[5(6)-benzimidazolyl]-2-aminoethanol (2), and of isoproterenol, (R,S)-1-[5(6)-benzimidazolyl]-2-isopropylaminoethanol (4). Compound 2 was shown to be a partial b...

journal_title：Journal of medicinal chemistry

authors： Arnett CD,Wright J,Zenker N

更新日期：1978-01-01 00:00:00

abstract：:AMPA receptors mediate fast excitatory synaptic transmission and are essential for synaptic plasticity. ANQX, a photoreactive AMPA receptor antagonist, is an important biological probe used to irreversibly inactivate AMPA receptors. Here, using X-ray crystallography and mass spectroscopy, we report that ANQX forms two...

journal_title：Journal of medicinal chemistry

authors： Cruz LA,Estébanez-Perpiñá E,Pfaff S,Borngraeber S,Bao N,Blethrow J,Fletterick RJ,England PM

更新日期：2008-09-25 00:00:00

abstract：:The endogenous peptides somatostatin (SRIF) and substance P comprise very different structures. Although both bind G-protein-coupled receptors, the SRIF receptors (SSTR 1-5) recognize SRIF and related peptides which retain its beta-turn such as the potent cyclic hexapeptide SRIF agonist L-363,301 (6a), but not substan...

journal_title：Journal of medicinal chemistry

authors： Hirschmann R,Yao W,Cascieri MA,Strader CD,Maechler L,Cichy-Knight MA,Hynes J Jr,van Rijn RD,Sprengeler PA,Smith AB 3rd

更新日期：1996-06-21 00:00:00

abstract：:As FDA-approved chemotherapeutic agents, cisplatin, oxaliplatin, and 5-fluorouracil are widely used in clinic but limited by severe side-effects. To ameliorate their respective defects, a series of "dual-prodrug" by linking oxoplatin and 5-FU were designed and synthesized. The assembled compounds 10-17, named Fuplatin...

journal_title：Journal of medicinal chemistry

authors： Zhang R,Song XQ,Liu RP,Ma ZY,Xu JY

更新日期：2019-05-09 00:00:00

abstract：:The levo and dextro isomers of 2,5-dimethyl-2'-hydroxy-9alpha- and -9beta-propyl-6,7-benzomorphans have been prepared. The analgesic potency and physical dependence capacity of the optical isomers and their racemic parents were determined. The 9alpha-propyl levo isomer was analgesically equipotent with morphine; the 9...

journal_title：Journal of medicinal chemistry

authors： Rice KC,Jacobson AE

更新日期：1976-03-01 00:00:00

abstract：:SHP-2, a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene, mediates cell signaling by growth factors and cytokines via the RAS/MAP kinase pathway. Somatic mutations in PTPN11 gene account for approximately 18% of juvenile myelomonocytic leukemia (JMML) patients. Moreover, SHP-2 mutations leading to ...

journal_title：Journal of medicinal chemistry

authors： Geronikaki A,Eleftheriou P,Vicini P,Alam I,Dixit A,Saxena AK

更新日期：2008-09-11 00:00:00

abstract：:The (E)-8-benzylidene and (E)-8-(3,4-dichlorobenzylidene), 7-ketone derivatives, 5 and 6, of the synthetic opiate 2-methyl-5-(3-hydroxyphenyl)morphan [5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1], were synthesized from the 7-ketone derivatives 2 or 4 via the Claisen-Schmidt reaction. The corresponding en...

journal_title：Journal of medicinal chemistry

authors： Bertha CM,Mattson MV,Flippen-Anderson JL,Rothman RB,Xu H,Cha XY,Becketts K,Rice KC

更新日期：1994-09-16 00:00:00

abstract：:Computational ADME (absorption, distribution, metabolism, and excretion) models may be used early in the drug discovery process in order to flag drug candidates with potentially problematic ADME profiles. We report the development, validation, and application of quantitative structure-property relationship (QSPR) mode...

journal_title：Journal of medicinal chemistry

authors： Shen M,Xiao Y,Golbraikh A,Gombar VK,Tropsha A

更新日期：2003-07-03 00:00:00