Discovery of Novel KRAS-PDEδ Inhibitors by Fragment-Based Drug Design.

abstract：:The olefinic dipeptide 5(S)-amino-7-methyl-3(E)-octenoic acid (1) was synthesized and used to make the olefinic peptides Leu psi [E-CH = CH]Gly-Val-Phe-OCH3 (2) and His-Leu psi [E-CH = CH]Gly-Val-Phe-OCH3 (3). These olefinic peptides were found to exhibit renin inhibitory activity against both hog kidney renin and hum...

journal_title：Journal of medicinal chemistry

authors： Johnson RL

更新日期：1984-10-01 00:00:00

abstract：:Monophenolic (2-(dipropylamino)indans and related compounds have been synthesized and tested for central dopamine-receptor stimulating activity, using biochemical and behavioral tests in rats and emesis tests in dogs. The active compounds possess similar relative potencies in eliciting the three different dopamine-rec...

journal_title：Journal of medicinal chemistry

authors： Hacksell U,Arvidsson LE,Svensson U,Nilsson JL,Wikström H,Lindberg P,Sanchez D,Hjorth S,Carlsson A,Paalzow L

更新日期：1981-04-01 00:00:00

abstract：:A novel series of optically active 2,6-disubstituted alkylphenols with improved anesthetic profiles compared to widely used propofol were synthesized. The incorporation of the cyclopropyl group not only increased the steric effect but also introduced stereoselective effects over their anesthetic properties. Compounds ...

journal_title：Journal of medicinal chemistry

authors： Qin L,Ren L,Wan S,Liu G,Luo X,Liu Z,Li F,Yu Y,Liu J,Wei Y

更新日期：2017-05-11 00:00:00

abstract：:Four novel potential prodrugs derived from daunorubicin (8, 10) and doxorubicin (12, 14) were designed and synthesized. They are self-immolative prodrugs for suicide gene therapy activation by the enzyme carboxypeptidase G2 (CPG2) subsequently releasing the corresponding anthracyclines, by a 1,6-elimination mechanism....

journal_title：Journal of medicinal chemistry

authors： Niculescu-Duvaz I,Niculescu-Duvaz D,Friedlos F,Spooner R,Martin J,Marais R,Springer CJ

更新日期：1999-07-01 00:00:00

abstract：:The potencies of a series of 2 beta-substituted cocaine analogues to displace [3H]-3 beta-(p-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester binding in rat striatal membranes demonstrate the requirement for a 2 beta-substituent with two hydrogen-bond acceptors. The insensitivity of the ester moiety to steric ...

journal_title：Journal of medicinal chemistry

authors： Lewin AH,Gao YG,Abraham P,Boja JW,Kuhar MJ,Carroll FI

更新日期：1992-01-01 00:00:00

abstract：:Necrosis is the main mode of cell death, which leads to multiple clinical conditions affecting hundreds of millions of people worldwide. Its molecular mechanisms are poorly understood, hampering therapeutics development. Here, we identify key proteolytic activities essential for necrosis using various biochemical appr...

journal_title：Journal of medicinal chemistry

authors： Khalfin B,Lichtenstein A,Albeck A,Nathan I

更新日期：2021-01-31 00:00:00

abstract：:The drug pentamidine inhibits calcium-dependent complex formation with p53 ((Ca)S100B·p53) in malignant melanoma (MM) and restores p53 tumor suppressor activity in vivo. However, off-target effects associated with this drug were problematic in MM patients. Structure-activity relationship (SAR) studies were therefore c...

journal_title：Journal of medicinal chemistry

authors： Cavalier MC,Ansari MI,Pierce AD,Wilder PT,McKnight LE,Raman EP,Neau DB,Bezawada P,Alasady MJ,Charpentier TH,Varney KM,Toth EA,MacKerell AD Jr,Coop A,Weber DJ

更新日期：2016-01-28 00:00:00

abstract：:Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATP-competitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds cov...

journal_title：Journal of medicinal chemistry

authors： Carmi C,Cavazzoni A,Vezzosi S,Bordi F,Vacondio F,Silva C,Rivara S,Lodola A,Alfieri RR,La Monica S,Galetti M,Ardizzoni A,Petronini PG,Mor M

更新日期：2010-03-11 00:00:00

abstract：:Hyperfibrinolytic situations can lead to life-threatening bleeding, especially during cardiac surgery. The approved antifibrinolytic agents such as tranexamic acid, ε-aminocaproic acid, 4-aminomethylbenzoic acid, and aprotinin were developed in the 1960s without the structural insight of their respective targets. Crys...

journal_title：Journal of medicinal chemistry

authors： Steinmetzer T,Pilgram O,Wenzel BM,Wiedemeyer SJA

更新日期：2020-02-27 00:00:00

abstract：:A series of 2-aminotetralins, substituted with a methoxy or a hydroxy group on the 5- or 7-position, and with varying N-alkyl or N-arylalkyl substituents, were prepared and evaluated in binding assays for human dopamine (DA) D2, D3, and D4 receptors. Some members of this series were prepared in former studies, but wer...

journal_title：Journal of medicinal chemistry

authors： van Vliet LA,Tepper PG,Dijkstra D,Damsma G,Wikström H,Pugsley TA,Akunne HC,Heffner TG,Glase SA,Wise LD

更新日期：1996-10-11 00:00:00

abstract：:A series of renin inhibitors have been prepared and evaluated for their susceptibility to cleavage by the serine protease chymotrypsin. The compounds were designed by consideration of the structural requirements in the active-site region of renin and chymotrypsin. By systematic alteration of the P3 phenylalanine resid...

journal_title：Journal of medicinal chemistry

authors： Plattner JJ,Marcotte PA,Kleinert HD,Stein HH,Greer J,Bolis G,Fung AK,Bopp BA,Luly JR,Sham HL

更新日期：1988-12-01 00:00:00

abstract：:Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in th...

journal_title：Journal of medicinal chemistry

authors： Watterson SH,De Lucca GV,Shi Q,Langevine CM,Liu Q,Batt DG,Beaudoin Bertrand M,Gong H,Dai J,Yip S,Li P,Sun D,Wu DR,Wang C,Zhang Y,Traeger SC,Pattoli MA,Skala S,Cheng L,Obermeier MT,Vickery R,Discenza LN,D'Arien

更新日期：2016-10-13 00:00:00

abstract：:A series of new highly chlorinated 1-methyleneallyl ("butadienyl") dialkyl phosphates and related phosphonates and phosphinates has been synthesized and assessed for anthelmintic activity in mice against the tapeworm Hymenolepis nana and the pinworm Syphacia obvelata. Highest activity was observed with diethyl 2,3,3-t...

journal_title：Journal of medicinal chemistry

authors： Pilgram K,Hass DK

更新日期：1975-12-01 00:00:00

abstract：:Protein tyrosine phosphatases (PTPases) are involved in the control of tyrosine phosphorylation levels in the cell and are believed to be crucial for the regulation of a multitude of cellular functions. A detailed understanding of the role played by PTPases in various signaling pathways has not yet been achieved, and ...

journal_title：Journal of medicinal chemistry

authors： Sarmiento M,Wu L,Keng YF,Song L,Luo Z,Huang Z,Wu GZ,Yuan AK,Zhang ZY

更新日期：2000-01-27 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：:A series of 4(6)- and 5-phenyl-substituted 2-amino- and 2-[(alkoxycarbonyl)amino]-1,4,5,6-tetrahydropyrimidines were prepared and evaluated for central nervous system (CNS) effects in animal models. Several 5-phenyl-substituted compounds possessed potent antidepressant activity and all compounds in this series were de...

journal_title：Journal of medicinal chemistry

authors： Weinhardt K,Wallach MB,Marx M

更新日期：1985-06-01 00:00:00

abstract：:5-Bromotryptophan (5-BrTrp) is the most potent amino acid derivative reported in the literature to inhibit the gelation of hemoglobin S (from sickle cell anemia patients). Trp-Trp is also more potent than Trp as an antigelation agent. Therefore, we have prepared a series of dipeptides containing 5-BrTrp and evaluated ...

journal_title：Journal of medicinal chemistry

authors： De Croos PZ,Sangdee P,Stockwell BL,Kar L,Thompson EB,Johnson ME,Currie BL

更新日期：1990-12-01 00:00:00

abstract：:The nature of the carbonyl and nitrogen substituents of hydroxamic acids has a major influence on the biological profile of these compounds. Hydroxamates with small groups such as methyl appended to the carbonyl and relatively large nitrogen substituents generally have longer duration in vivo, produce greater plasma c...

journal_title：Journal of medicinal chemistry

authors： Summers JB,Gunn BP,Martin JG,Martin MB,Mazdiyasni H,Stewart AO,Young PR,Bouska JB,Goetze AM,Dyer RD

更新日期：1988-10-01 00:00:00

abstract：:The cytotoxic complex, [PtCl(Am)2(ACRAMTU)](NO3)2 (1) ((Am)2 = ethane-1,2-diamine, en; ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea), is a dual platinating/intercalating DNA binder that, unlike clinical platinum agents, does not induce DNA cross-links. Here, we demonstrate that substitution of the thi...

journal_title：Journal of medicinal chemistry

authors： Ma Z,Choudhury JR,Wright MW,Day CS,Saluta G,Kucera GL,Bierbach U

更新日期：2008-12-11 00:00:00

abstract：:A new structurally distinct class of 14-membered-ring macrolides is characterized by a keto-function instead of the cladinose sugar, well-known for its fragility even in weakly acidic media. This new class called ketolides is endowed with remarkable antibacterial activity against macrolide-resistant strains. A complet...

journal_title：Journal of medicinal chemistry

authors： Bertho G,Gharbi-Benarous J,Delaforge M,Lang C,Parent A,Girault JP

更新日期：1998-08-27 00:00:00

abstract：:N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a-g can exist in conformations w...

journal_title：Journal of medicinal chemistry

authors： Carroll FI,Chaudhari S,Thomas JB,Mascarella SW,Gigstad KM,Deschamps J,Navarro HA

更新日期：2005-12-29 00:00:00

abstract：:We explore the significance of pi-cation interactions in the binding of ligands to nicotinic acetylcholine receptors. Specifically, the Austin method of semiempirical molecular orbital theory is utilized to estimate the interaction of aromatic amino acid side chains with the cation-containing heterocyclic ring fragmen...

journal_title：Journal of medicinal chemistry

authors： Schmitt JD,Sharples CG,Caldwell WS

更新日期：1999-08-12 00:00:00

abstract：:A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDA...

journal_title：Journal of medicinal chemistry

authors： Marson CM,Matthews CJ,Atkinson SJ,Lamadema N,Thomas NS

更新日期：2015-09-10 00:00:00

abstract：:Compound 1 (1-benzyl-3-methyl-4-[4-(4-fluorophenyl)-4-oxobutyl]piperazine), a synthetic intermediate identified as a potential atypical antipsychotic, was selected as the starting point for pharmacological improvement. From 1, sequential structural variations were conducted in order to improve its potency and oral bio...

journal_title：Journal of medicinal chemistry

authors： Bolós J,Gubert S,Anglada L,Planas JM,Burgarolas C,Castelló JM,Sacristán A,Ortiz JA

更新日期：1996-07-19 00:00:00

abstract：:Two natural occurring melanotropins, camel betaC2-MSH and bovine beta-MSH, have been synthesized by improved solid-phase procedures. The coupling reaction of tert-butyloxycarbonylamino acids was achieved by using their preformed symmetrical anhydrides. The synthetic hormones were purified by gel filtration on Sephadex...

journal_title：Journal of medicinal chemistry

authors： Lemaire S,Yamashiro D,Li CH

更新日期：1976-03-01 00:00:00

abstract：:A new class of substituted 1-phenyl-3-piperazinyl-2-propanones with antimuscarinic activity is reported. As part of a structure-activity relationship study of this class, various structural modifications, particularly ones involving substitution of position 1 and the terminal piperazine nitrogen, were investigated. Th...

journal_title：Journal of medicinal chemistry

authors： Kaiser C,Audia VH,Carter JP,McPherson DW,Waid PP,Lowe VC,Noronha-Blob L

更新日期：1993-03-05 00:00:00

abstract：:The retinoid 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) and its active analogues induce cell-cycle arrest and programmed cell death (apoptosis) in cancer cells independently of retinoic acid receptor (RAR) interaction. Its analogue, (E)-4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-(3'-acetami...

journal_title：Journal of medicinal chemistry

authors： Dawson MI,Harris DL,Liu G,Hobbs PD,Lange CW,Jong L,Bruey-Sedano N,James SY,Zhang XK,Peterson VJ,Leid M,Farhana L,Rishi AK,Fontana JA

更新日期：2004-07-01 00:00:00

abstract：:Studies of molecular structure-carcinogenicity relations for a set of 157 aromatic amines are reported. A computer-assisted approach using pattern-recognition methods was used to develop a series of discriminants for aromatic amino carcinogenic potential. The 157 compounds were divided into subsets according to tumor ...

journal_title：Journal of medicinal chemistry

authors： Yuta K,Jurs PC

更新日期：1981-03-01 00:00:00

abstract：:It is common practice to calculate large numbers of molecular descriptors, apply variable selection procedures to reduce the numbers, and then construct multiple linear regression (MLR) models with biological activity. The significance of these models is judged using the usual statistical tests. Unfortunately, these t...

journal_title：Journal of medicinal chemistry

authors： Livingstone DJ,Salt DW

更新日期：2005-02-10 00:00:00

abstract：:Anaplastic lymphoma kinase (ALK) is a valid target for anticancer therapy; however, potent ALK inhibitors suitable for clinical use are lacking. Because the majority of described kinase inhibitors bind in the ATP pocket of the kinase domain, we have characterized this pocket in ALK using site-directed mutagenesis, inh...

journal_title：Journal of medicinal chemistry

authors： Gunby RH,Ahmed S,Sottocornola R,Gasser M,Redaelli S,Mologni L,Tartari CJ,Belloni V,Gambacorti-Passerini C,Scapozza L

更新日期：2006-09-21 00:00:00