Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift.

abstract：:Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding m...

journal_title：Journal of medicinal chemistry

authors： Patel S,Cohen F,Dean BJ,De La Torre K,Deshmukh G,Estrada AA,Ghosh AS,Gibbons P,Gustafson A,Huestis MP,Le Pichon CE,Lin H,Liu W,Liu X,Liu Y,Ly CQ,Lyssikatos JP,Ma C,Scearce-Levie K,Shin YG,Solanoy H,Stark KL,Wa

更新日期：2015-01-08 00:00:00

abstract：:A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility. E...

journal_title：Journal of medicinal chemistry

authors： Borthwick AD,Liddle J,Davies DE,Exall AM,Hamlett C,Hickey DM,Mason AM,Smith IE,Nerozzi F,Peace S,Pollard D,Sollis SL,Allen MJ,Woollard PM,Pullen MA,Westfall TD,Stanislaus DJ

更新日期：2012-01-26 00:00:00

abstract：:A novel series of ligands with substitutions at the 5-position on phenyl ring A and at the 4'-position on phenyl ring B of 2-(2'-((dimethylamino)methyl)-4'-(fluoroalkoxy)phenylthio)benzenamine (4'-2-fluoroethoxy derivatives 28-31 and 4'-3-fluoropropoxy derivatives 40-42) were prepared and tested as serotonin transport...

journal_title：Journal of medicinal chemistry

authors： Parhi AK,Wang JL,Oya S,Choi SR,Kung MP,Kung HF

更新日期：2007-12-27 00:00:00

abstract：:A series of derivatives of the antimycobacterial natural product pyridomycin have been prepared with the C2 side chain attached to the macrocyclic core structure by a C-C single bond, in place of the synthetically more demanding enol ester double bond found in the natural product. Hydrophobic C2 substituents of suffic...

journal_title：Journal of medicinal chemistry

authors： Kienle M,Eisenring P,Stoessel B,Horlacher OP,Hasler S,van Colen G,Hartkoorn RC,Vocat A,Cole ST,Altmann KH

更新日期：2020-02-13 00:00:00

abstract：:Inhibition of the menin-mixed lineage leukemia (MLL) protein-protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the me...

journal_title：Journal of medicinal chemistry

authors： Aguilar A,Zheng K,Xu T,Xu S,Huang L,Fernandez-Salas E,Liu L,Bernard D,Harvey KP,Foster C,McEachern D,Stuckey J,Chinnaswamy K,Delproposto J,Kampf JW,Wang S

更新日期：2019-07-11 00:00:00

abstract：:New fluorinated 2-aryl-benzothiazoles, -benzoxazoles, and -chromen-4-ones have been synthesized and their activity against MCF-7 and MDA 468 breast cancer cell lines compared with the potent antitumor benzothiazole 5. Analogues such as 9a, b and 12a, d yielded submicromolar GI50 values in both cell lines; however, non...

journal_title：Journal of medicinal chemistry

authors： Aiello S,Wells G,Stone EL,Kadri H,Bazzi R,Bell DR,Stevens MF,Matthews CS,Bradshaw TD,Westwell AD

更新日期：2008-08-28 00:00:00

abstract：:Taking advantage of a proposed hydrophobic region on 5-HT2 receptors previously identified by radioligand-binding studies utilizing various phenylisopropylamine derivatives, we prepared and evaluated several N1 - and/or C7-alkyl-substituted derivatives of alpha-methyltryptamine in order to improve its affinity and sel...

journal_title：Journal of medicinal chemistry

authors： Glennon RA,Chaurasia C,Titeler M

更新日期：1990-10-01 00:00:00

abstract：:The AAA+ ATPase, p97, also referred to as VCP, plays an essential role in cellular homeostasis by regulating endoplasmic reticulum-associated degradation (ERAD), mitochondrial-associated degradation (MAD), chromatin-associated degradation, autophagy, and endosomal trafficking. Mutations in p97 have been linked to a nu...

journal_title：Journal of medicinal chemistry

authors： Huryn DM,Kornfilt DJP,Wipf P

更新日期：2020-03-12 00:00:00

abstract：:We have previously shown [Cys-Trp-Arg-Nva-Arg-Tyr-NH(2)](2), 1, to be a moderately selective neuropeptide Y (NPY) Y(4) receptor agonist. Toward improving the selectivity and potency for Y(4) receptors, we studied the effects of dimerizing H-Trp-Arg-Nva-Arg-Tyr-NH(2) using various diamino-dicarboxylic acids containing ...

journal_title：Journal of medicinal chemistry

authors： Balasubramaniam A,Mullins DE,Lin S,Zhai W,Tao Z,Dhawan VC,Guzzi M,Knittel JJ,Slack K,Herzog H,Parker EM

更新日期：2006-04-20 00:00:00

abstract：:The major mechanism by which the serotonin neurotoxin 5,6-dihydroxytryptamine (5,6-DHT) expresses its neurodegenerative action may involve alkylation of biological nucleophiles by the electrophilic quinoid autoxidation products. To determine the relative importance of various sites on these autoxidation products towar...

journal_title：Journal of medicinal chemistry

authors： Sinhababu AK,Ghosh AK,Borchardt RT

更新日期：1985-09-01 00:00:00

abstract：:The synthesis and biological activity of a novel cyclic beta-sheet-type antimicrobial dehydropeptide based on gramicidin S (GS) is described. The GS analogue, containing two (Z)-(beta-3-pyridyl)-alpha,beta-dehydroalanine (DeltaZ3Pal) residues at the 4 and 4' positions (2), was synthesized by solution-phase methodologi...

journal_title：Journal of medicinal chemistry

authors： Yamada K,Shinoda SS,Oku H,Komagoe K,Katsu T,Katakai R

更新日期：2006-12-28 00:00:00

abstract：:We previously reported that (+/-)-6-(4-(benzylamino)-7-quinazolinyl)-4,5- dihydro-5-methyl-3(2H)-pyridazinone (+/-)-1, KF15232) showed potent cardiotonic activity with a strong myofibrillar Ca(2+)-sensitizing effect. As an extension of our work, we attempted to synthesize optically active 1. (+/-)-4-(4-(Benzylamino)-7...

journal_title：Journal of medicinal chemistry

authors： Nomoto Y,Takai H,Ohno T,Nagashima K,Yao K,Yamada K,Kubo K,Ichimura M,Mihara A,Kase H

更新日期：1996-01-05 00:00:00

abstract：:Glycosylated β-endorphin analogues of various amphipathicity were studied in vitro and in vivo in mice. Opioid binding affinities of the O-linked glycopeptides (mono- or disaccharides) and unglycosylated peptide controls were measured in human receptors expressed in CHO cells. All were pan-agonists, binding to μ-, δ-,...

journal_title：Journal of medicinal chemistry

authors： Li Y,St Louis L,Knapp BI,Muthu D,Anglin B,Giuvelis D,Bidlack JM,Bilsky EJ,Polt R

更新日期：2014-03-27 00:00:00

abstract：:New linear and cyclic guanidines were synthesized and tested in vitro for their antifungal activity toward clinically relevant strains of Candida species, in comparison to fluconazole. Macrocyclic compounds showed a minimum inhibitory concentration in the micromolar range and a biological activity profile in some case...

journal_title：Journal of medicinal chemistry

authors： Manetti F,Castagnolo D,Raffi F,Zizzari AT,Rajamäki S,D'Arezzo S,Visca P,Cona A,Fracasso ME,Doria D,Posteraro B,Sanguinetti M,Fadda G,Botta M

更新日期：2009-12-10 00:00:00

abstract：:Three [5-t-BuPro(7)]oxytocin analogues were synthesized by substituting (2S,5R)-5-tert-butylproline for proline in oxytocin, [Mpa(1)]oxytocin, and [dPen(1)]oxytocin. Relative to oxytocin, [5-t-BuPro(7)]oxytocin and [Mpa(1),5-t-BuPro(7)]oxytocin exhibited strongly reduced binding affinity to the receptor; however, both...

journal_title：Journal of medicinal chemistry

authors： Bélec L,Slaninova J,Lubell WD

更新日期：2000-04-20 00:00:00

abstract：:Novel neplanocin A analogues modified at the 6'-position, i.e., 6'-deoxy analogues (2, 3, 6, 9, 20), 6'-O-methylneplanocin A (15), and 6'-C-methylneplanocin A's (22a and 22b) have been synthesized and evaluated for their antiviral activity in a wide variety of DNA and RNA virus systems. These compounds showed an activ...

journal_title：Journal of medicinal chemistry

authors： Shuto S,Obara T,Toriya M,Hosoya M,Snoeck R,Andrei G,Balzarini J,De Clercq E

更新日期：1992-01-24 00:00:00

abstract：:Lysosomotropic detergents, which kill mammalian cells by disrupting lysosomal membranes, have now been found to be antifungals also. All strains in our assay are susceptible. The mode of action is as yet undetermined, but intracellular vacuoles may be the primary targets. ...

journal_title：Journal of medicinal chemistry

authors： Firestone RA,Pisano JM,Garrity GM,Fromtling RA,Zimmerman SB

更新日期：1987-08-01 00:00:00

abstract：:(N)-Methanocarba nucleosides containing bicyclo[3.1.0]hexane replacement of the ribose ring previously demonstrated selectivity as A(3) adenosine receptor (AR) agonists (5'-uronamides) or antagonists (5'-truncated). Here, these two series were modified in parallel at the adenine C2 position. N(6)-3-Chlorobenzyl-5'-N-m...

journal_title：Journal of medicinal chemistry

authors： Tosh DK,Chinn M,Ivanov AA,Klutz AM,Gao ZG,Jacobson KA

更新日期：2009-12-10 00:00:00

abstract：:A structure-activity analysis of peptides containing backbone C alpha-methyl modification at the P4 site of the angiotensinogen sequence led to the discovery of potent renin inhibitors with apparent in vitro metabolic stability. Boc-alpha-MePro-Phe-His-Leu psi[CHOHCH2]Val-Ile-Amp dicitrate (Va) is a potent inhibitor o...

journal_title：Journal of medicinal chemistry

authors： Thaisrivongs S,Pals DT,Lawson JA,Turner SR,Harris DW

更新日期：1987-03-01 00:00:00

abstract：:A new series of 11-[(aminoalkyl)carbonyl] derivatives of 6,11-dihydrodibenzo[c,f][1,2,5]thiadiazepine 5,5-dioxide (10-39) were synthesized and evaluated for potential antidepressant activity in the apomorphine-induced hypothermia (Apo 16) test. Effects on reserpine-induced hypothermia and toxicity for the most potent ...

journal_title：Journal of medicinal chemistry

authors： Giannotti D,Viti G,Sbraci P,Pestellini V,Volterra G,Borsini F,Lecci A,Meli A,Dapporto P,Paoli P

更新日期：1991-04-01 00:00:00

abstract：:The previous paper reported on the synthesis and pharmacological evaluation of N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives, from among which three compounds were selected as potent potassium-channel openers. In the present study, selected compounds were tested for antagonism of potassium-induce...

journal_title：Journal of medicinal chemistry

authors： Eda M,Takemoto T,Ono S,Okada T,Kosaka K,Gohda M,Matzno S,Nakamura N,Fukaya C

更新日期：1994-06-24 00:00:00

abstract：:The N-demethylation of 1-(N-methyl-N-trideuteriomethylamino)-3-phenylpropane (1) by rodent liver homogenates was studied. The ratio of 1-trideuteriomethylamino-3-phenylpropane (2)/1-methylamino-3-phenylpropane (3) was determined by gc-ms. The ratio of 2/3 in the product of N-demethylation of 1 by liver homogenate from...

journal_title：Journal of medicinal chemistry

authors： Abdel-Monem MM

更新日期：1975-04-01 00:00:00

abstract：:4-(2-Methoxyphenyl)-2-[4(5)-methyl-5(4)-imidazolylmethyl]thiazole (5) is a highly potent member of a structurally novel series of selective serotonin-3 receptor antagonists. The synthesis of tritiated 5 and its binding profile in neuroblastoma-glioma 108-15 cells are described. Furthermore, in vivo studies in rat with...

journal_title：Journal of medicinal chemistry

authors： Rosen T,Seeger TF,McLean S,Nagel AA,Ives JL,Guarino KJ,Bryce D,Furman J,Roth RW,Chalabi PM

更新日期：1990-11-01 00:00:00

abstract：:A series of 1-aminopropan-2-ols were synthesized and evaluated against two strains of malaria, Plasmodium falciparum FCR3 (chloroquine-resistant) and 3D7 (chloroquine-sensitive). Microwave-assisted ring opening of epoxides (aryl and alkyl glycidyl ethers, glycidol, epichlorohydrin) with various amines without catalyst...

journal_title：Journal of medicinal chemistry

authors： Robin A,Brown F,Bahamontes-Rosa N,Wu B,Beitz E,Kun JF,Flitsch SL

更新日期：2007-08-23 00:00:00

abstract：:1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprot...

journal_title：Journal of medicinal chemistry

authors： Rombouts FJ,Tresadern G,Delgado O,Martínez-Lamenca C,Van Gool M,García-Molina A,Alonso de Diego SA,Oehlrich D,Prokopcova H,Alonso JM,Austin N,Borghys H,Van Brandt S,Surkyn M,De Cleyn M,Vos A,Alexander R,Macdonald G,Mo

更新日期：2015-10-22 00:00:00

abstract：:We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this a...

journal_title：Journal of medicinal chemistry

authors： Nishimura Y,Esaki T,Isshiki Y,Furuta Y,Mizutani A,Kotake T,Emura T,Watanabe Y,Ohta M,Nakagawa T,Ogawa K,Arai S,Noda H,Kitamura H,Shimizu M,Tamura T,Sato H

更新日期：2020-05-28 00:00:00

abstract：:A series of 6,7-dichloro-1,4-dihydro-(1H, 4H)-quinoxaline-2,3-diones (1-17) were prepared in which the 5-position substituent was a heterocyclylmethyl or 1-(heterocyclyl)-1-propyl group. Structure-activity relationships were evaluated where binding affinity for the glycine site of the N-methyl-D-aspartate (NMDA) recep...

journal_title：Journal of medicinal chemistry

authors： Fray MJ,Bull DJ,Carr CL,Gautier EC,Mowbray CE,Stobie A

更新日期：2001-06-07 00:00:00

abstract：:We have reported the preparation and anticancer evaluation of certain 4-anilinofuro[2,3-b]quinolines. However, drawbacks such as lack of selective cytotoxicity, poor oral bioavailability, and poor water solubility exhibited by these compounds prompted us to search for newer derivatives. Among them, (E)-1-(4-(furo[2,3-...

journal_title：Journal of medicinal chemistry

authors： Chen YW,Chen YL,Tseng CH,Liang CC,Yang CN,Yao YC,Lu PJ,Tzeng CC

更新日期：2011-07-14 00:00:00

abstract：:Starting from the high-throughput screening hit 1a, novel cathepsin K inhibitors have been developed based on a purine scaffold. High-resolution X-ray structures of several derivatives have revealed the binding mode of these unique cysteine protease inhibitors. ...

journal_title：Journal of medicinal chemistry

authors： Altmann E,Cowan-Jacob SW,Missbach M

更新日期：2004-11-18 00:00:00

abstract：:By use of the effectively cleaved beta-secretase (BACE) substrate (1), incorporation of a statine in P(1) resulted in a weak inhibitor 13 of the enzyme. Further substitution of P(1)'-Asp by P(1)'-Val in 13 results in a potent inhibitor 22 of BACE. Removal of the P(10)-P(5) residues on the N-terminal part of inhibitor ...

journal_title：Journal of medicinal chemistry

authors： Tung JS,Davis DL,Anderson JP,Walker DE,Mamo S,Jewett N,Hom RK,Sinha S,Thorsett ED,John V

更新日期：2002-01-17 00:00:00