Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101).

abstract：:Significant efforts have been reported on the development of influenza antivirals including inhibitors of the RNA-dependent RNA polymerase PA N-terminal (PAN) endonuclease. Based on recently identified, highly active metal-binding pharmacophores (MBPs) for PAN endonuclease inhibition, a fragment-based drug development...

journal_title：Journal of medicinal chemistry

authors： Credille CV,Morrison CN,Stokes RW,Dick BL,Feng Y,Sun J,Chen Y,Cohen SM

更新日期：2019-11-14 00:00:00

abstract：:The intracellular delivery of nucleic acid molecules is a complex process involving several distinct steps; among these the endosomal escape appeared to be of particular importance for an efficient protein production (or inhibition) into host cells. In the present study, a new series of ionizable vectors, derived from...

journal_title：Journal of medicinal chemistry

authors： Habrant D,Peuziat P,Colombani T,Dallet L,Gehin J,Goudeau E,Evrard B,Lambert O,Haudebourg T,Pitard B

更新日期：2016-04-14 00:00:00

abstract：:Four novel steroidal alpha-methylene delta-lactones have been synthesized and shown to be active against human nasopharyngeal carcinoma (KB) cells in culture. The syntheses involved the use of known alpha-methylenation procedures. In addition, the lactone 6 was directly methylenated by reaction with CH2O/KOH or Et2NH/...

journal_title：Journal of medicinal chemistry

authors： Dehal SS,Marples BA,Stretton RJ,Traynor JR

更新日期：1980-01-01 00:00:00

abstract：:HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimizatio...

journal_title：Journal of medicinal chemistry

authors： Jiang Y,Andrews SW,Condroski KR,Buckman B,Serebryany V,Wenglowsky S,Kennedy AL,Madduru MR,Wang B,Lyon M,Doherty GA,Woodard BT,Lemieux C,Geck Do M,Zhang H,Ballard J,Vigers G,Brandhuber BJ,Stengel P,Josey JA,Beigelm

更新日期：2014-03-13 00:00:00

abstract：:A series of Ala and Aoc analogues of (-)-ternatin were prepared, and their bioactivities were assessed by a fat-accumulation inhibition assay using 3T3-L1 adipocytes, which led to the discovery of key structure-activity relationships (SAR). ...

journal_title：Journal of medicinal chemistry

authors： Shimokawa K,Iwase Y,Miwa R,Yamada K,Uemura D

更新日期：2008-10-09 00:00:00

abstract：:We disclose optimization efforts based on the novel non-nucleoside adenosine deaminase (ADA) inhibitor, 4 (K(i) = 680 nM). Structure-based drug design utilizing the crystal structure of the 4/ADA complex led to discovery of 5 (K(i) = 11 nM, BA = 30% in rats). Furthermore, from metabolic considerations, we discovered t...

journal_title：Journal of medicinal chemistry

authors： Terasaka T,Okumura H,Tsuji K,Kato T,Nakanishi I,Kinoshita T,Kato Y,Kuno M,Seki N,Naoe Y,Inoue T,Tanaka K,Nakamura K

更新日期：2004-05-20 00:00:00

abstract：:Here, we report the synthesis of a designed multi-pharmacophore ligand derived from the linkage of a delta selective peptide antagonist (Dmt-Tic) and a mu/kappa morphinan agonist butorphan (MCL 101) through a two methylene spacer. The new compound MCL 450 maintains the same characteristics as those the two reference c...

journal_title：Journal of medicinal chemistry

authors： Neumeyer JL,Peng X,Knapp BI,Bidlack JM,Lazarus LH,Salvadori S,Trapella C,Balboni G

更新日期：2006-09-07 00:00:00

abstract：:A primary goal of lead optimization is to identify compounds with improved absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. A number of reports have linked computed molecular properties to desirable in vivo ADMET outcomes, but a significant limitation of these analyses is the failure t...

journal_title：Journal of medicinal chemistry

authors： Sutherland JJ,Raymond JW,Stevens JL,Baker TK,Watson DE

更新日期：2012-07-26 00:00:00

abstract：:UDP and UDP-glucose activate the P2Y14 receptor (P2Y14R) to modulate processes related to inflammation, diabetes, and asthma. A computational pipeline suggested alternatives to naphthalene of a previously reported P2Y14R antagonist (3, PPTN) using docking and molecular dynamics simulations on a hP2Y14R homology model ...

journal_title：Journal of medicinal chemistry

authors： Junker A,Balasubramanian R,Ciancetta A,Uliassi E,Kiselev E,Martiriggiano C,Trujillo K,Mtchedlidze G,Birdwell L,Brown KA,Harden TK,Jacobson KA

更新日期：2016-07-14 00:00:00

abstract：:We have introduced topographical constraints at the 9 position of a superpotent cyclic alpha-melanotropin analogue, Ac-Nle4-Asp5-His6-DPhe7-Arg8-Trp9-Lys10-NH2, by incorporating a methyl group at the beta-carbon of Trp9. These studies were performed on the Trp side chain pharmacophore to identify the bioactive topogra...

journal_title：Journal of medicinal chemistry

authors： Haskell-Luevano C,Boteju LW,Miwa H,Dickinson C,Gantz I,Yamada T,Hadley ME,Hruby VJ

更新日期：1995-11-10 00:00:00

abstract：:Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previous...

journal_title：Journal of medicinal chemistry

authors： Qin J,Rajaratnam R,Feng L,Salami J,Barber-Rotenberg JS,Domsic J,Reyes-Uribe P,Liu H,Dang W,Berger SL,Villanueva J,Meggers E,Marmorstein R

更新日期：2015-01-08 00:00:00

abstract：:6-Substituted 6-deoxy-L-galactose (L-fucose) derivatives were synthesized as potential antimetabolites of L-fucose. The cytotoxic effects of these compounds were evaluated on P388 leukemia cells in culture. The L-fucose analogues which showed the most potent growth inhibition were the sulfonyl ester, bromo, and iodo d...

journal_title：Journal of medicinal chemistry

authors： May JA Jr,Sartorelli AC

更新日期：1979-08-01 00:00:00

abstract：:We have synthesized several 7alpha-fluoro (F) and 7alpha-iodo (I) analogues of 5alpha-dihydrotestosterone (5alpha-DHT) and 19-nor-5alpha-dihydrotestosterone (5alpha-NDHT) and tested them for binding to the androgen receptor and for their biological activity in an in vitro assay with cells that have been engineered to ...

journal_title：Journal of medicinal chemistry

authors： Labaree DC,Hoyte RM,Nazareth LV,Weigel NL,Hochberg RB

更新日期：1999-06-03 00:00:00

abstract：:In order to investigate the structural requirements for gastroprotective activity in 6-[[1(S)-(3(S),4-dihydro-8- hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]amino]-4(S),5(S)-dihydroxy 6-oxo-3(S)-ammoniohexanoate [AI-77-B, 1], a product of Bacillus pumilus AI-77, nine derivatives were prepared and then tested for...

journal_title：Journal of medicinal chemistry

authors： Shimojima Y,Hayashi H

更新日期：1983-10-01 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：:Recently we have described the antitumor activities of 2-benzoxazolylhydrazones derived from 2-formyl and 2-acetylpyridines. In search of a more efficacious analogue, compounds in which the 2-acetylpyridine moiety has been replaced by 2-acylpyridine and alpha-(N)-acetyldiazine/quinoline groups have been synthesized. T...

journal_title：Journal of medicinal chemistry

authors： Easmon J,Pürstinger G,Thies KS,Heinisch G,Hofmann J

更新日期：2006-10-19 00:00:00

abstract：:Cysteine proteases play an important role in cell migration and tumor metastasis. Therefore, their inhibitors are of colossal interest, having potential to be developed as effective antimetastatic drugs for tumor chemotherapy. Traditionally, secondary metabolites from streptomyces show a wide range of diversity with r...

journal_title：Journal of medicinal chemistry

authors： Singh JP,Tamang S,Rajamohanan PR,Jima NC,Chakraborty G,Kundu GC,Gaikwad SM,Khan MI

更新日期：2010-07-22 00:00:00

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

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

abstract：:(4-Methoyx-2,3,6-trimethylphenyl)nonatetraenoic acids, esters, and amides (analogues of retinoic acid) bearing a fluorine atom(s) or a trifluoromethyl group on the polyene side chain were synthesized. The biological activities of these compounds and of 10-, 12-, and 14-fluororetinoic acid esters were evaluated in vivo...

journal_title：Journal of medicinal chemistry

authors： Pawson BA,Chan KK,DeNoble J,Han RJ,Piermattie V,Specian AC,Srisethnil S,Trown PW,Bohoslawec O,Machlin LJ,Gabriel E

更新日期：1979-09-01 00:00:00

abstract：:A series of 2,2'-disubstituted 5,5'-dibenzimidazolyl ketones and related compounds have been synthesized of which 2,2'-bis(carbomethoxyamino)-5,5'-dibenzimidazolyl ketone exhibited a broad spectrum of anthelmintic activity in experimental animals. At doses of 10-50 mg/kg given intraperitoneally, 5 killed 100% of the a...

journal_title：Journal of medicinal chemistry

authors： Abuzar S,Sharma S,Fatma N,Gupta S,Murthy PK,Katiyar JC,Chatterjee RK,Sen AB

更新日期：1986-07-01 00:00:00

abstract：:Following earlier work on cystine-bridged peptides, cyclic phosphopeptides containing nonreducible mimics of cystine were synthesized that show high affinity and specificity toward the Src homology (SH2) domain of the growth factor receptor-binding protein (Grb2). Replacement of the cystine in the cyclic heptapeptide ...

journal_title：Journal of medicinal chemistry

authors： Ettmayer P,France D,Gounarides J,Jarosinski M,Martin MS,Rondeau JM,Sabio M,Topiol S,Weidmann B,Zurini M,Bair KW

更新日期：1999-03-25 00:00:00

abstract：:A simple pharmacophore point filter has been developed that discriminates between drug-like and nondrug-like chemical matter. It is based on the observation that nondrugs are often underfunctionalized. Therefore, a minimum count of well-defined pharmacophore points is required to pass the filter. The application of th...

journal_title：Journal of medicinal chemistry

authors： Muegge I,Heald SL,Brittelli D

更新日期：2001-06-07 00:00:00

abstract：:In 1869, Crum Brown discovered the first structure-activity link by showing that alkaloids, even convulsive ones, were converted by N-methylation to muscle relaxants resembling curarine (itself a quaternary amine). This led to an attempt to link every type of drug action to its own cluster of atoms. This quest was jol...

journal_title：Journal of medicinal chemistry

authors： Albert A

更新日期：1982-01-01 00:00:00

abstract：:Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A ...

journal_title：Journal of medicinal chemistry

authors： Liu YA,Jin Q,Zou Y,Ding Q,Yan S,Wang Z,Hao X,Nguyen B,Zhang X,Pan J,Mo T,Jacobsen K,Lam T,Wu TY,Petrassi HM,Bursulaya B,DiDonato M,Gordon WP,Liu B,Baaten J,Hill R,Nguyen-Tran V,Qiu M,Zhang YQ,Kamireddy A,

更新日期：2020-03-26 00:00:00

abstract：:A new paradigm for drug research has emerged, namely the deliberate search for molecules able to selectively affect the proliferation, differentiation, and migration of adult stem cells within the tissues in which they exist. Recently, there has been significant interest in medicinal chemistry toward the discovery and...

journal_title：Journal of medicinal chemistry

authors： Davies SG,Kennewell PD,Russell AJ,Seden PT,Westwood R,Wynne GM

更新日期：2015-04-09 00:00:00

abstract：:The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold...

journal_title：Journal of medicinal chemistry

authors： Li Z,Xiao S,Yang Y,Chen C,Lu T,Chen Z,Jiang H,Chen S,Luo C,Zhou B

更新日期：2020-04-23 00:00:00

abstract：:The gold(I) complexes of the general formula [Au(L(n))(PPh(3))]·xH(2)O (1-8; n = 1-8 and x = 0-1.5), where L(n) stands for a deprotonated form of the benzyl-substituted derivatives of 6-benzylaminopurine, were prepared, thoroughly characterized (elemental analyses, FT-IR, Raman and multinuclear NMR spectroscopy, ESI+ ...

journal_title：Journal of medicinal chemistry

authors： Trávníček Z,Starha P,Vančo J,Silha T,Hošek J,Suchý P Jr,Pražanová G

更新日期：2012-05-24 00:00:00

abstract：:The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glio...

journal_title：Journal of medicinal chemistry

authors： Rais R,Jančařík A,Tenora L,Nedelcovych M,Alt J,Englert J,Rojas C,Le A,Elgogary A,Tan J,Monincová L,Pate K,Adams R,Ferraris D,Powell J,Majer P,Slusher BS

更新日期：2016-09-22 00:00:00

abstract：:A cell-free assay was developed for the orphan nuclear receptor LXRalpha that measures the ligand-dependent recruitment of a peptide from the steroid receptor coactivator 1 (SRC1) to the nuclear receptor. Using this ligand-sensing assay (LiSA), the structural requirements for activation of the receptor by oxysterols a...

journal_title：Journal of medicinal chemistry

authors： Spencer TA,Li D,Russel JS,Collins JL,Bledsoe RK,Consler TG,Moore LB,Galardi CM,McKee DD,Moore JT,Watson MA,Parks DJ,Lambert MH,Willson TM

更新日期：2001-03-15 00:00:00

abstract：:A series of hexadeoxyribonucleotides (6-mers), d(TGGGAG), substituted with a variety of aromatic groups at the 5'-end were synthesized and tested for anti-human immunodeficiency virus type 1 (HIV-1) activity. While unmodified d(TGGGAG) (31) had no anti-HIV-1 activity, compound 23 with a 3,4-di(benzyloxy)benzyl (DBB) g...

journal_title：Journal of medicinal chemistry

authors： Hotoda H,Koizumi M,Koga R,Kaneko M,Momota K,Ohmine T,Furukawa H,Agatsuma T,Nishigaki T,Sone J,Tsutsumi S,Kosaka T,Abe K,Kimura S,Shimada K

更新日期：1998-09-10 00:00:00