Abstract：
:Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P(4) moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Quan ML,Lam PY,Han Q,Pinto DJ,He MY,Li R,Ellis CD,Clark CG,Teleha CA,Sun JH,Alexander RS,Bai S,Luettgen JM,Knabb RM,Wong PC,Wexler RRdoi
10.1021/jm0497949keywords:
subject
Has Abstractpub_date
2005-03-24 00:00:00pages
1729-44issue
6eissn
0022-2623issn
1520-4804journal_volume
48pub_type
杂志文章abstract：:The crystal and molecular structure of metyrapone, a powerful inhibitor of certain cytochromes P-450, is described. Cytochrome P-450 enzymes are involved in metabolic processes, including those activating insecticides, drugs, and carcinogens. Metyrapone inhibits both the adrenal cytochrome P-450 catalyzing 11-beta-hyd...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00363a008
更新日期：1983-09-01 00:00:00
abstract：:The oxazolidinone antibacterials target the 50S subunit of prokaryotic ribosomes. To gain insight into their mechanism of action, the crystal structure of the canonical oxazolidinone, linezolid, has been determined bound to the Haloarcula marismortui 50S subunit. Linezolid binds the 50S A-site, near the catalytic cent...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800379d
更新日期：2008-06-26 00:00:00
abstract：:A series of substituted analogues based on the novel 2,3-dihydro-6-hydroxypyrimido[2,1-f]purine-4,8(1H,9H)-dione ring system have been synthesized and shown to exhibit antiinflammatory activity in the adjuvant-induced arthritis rat model (AAR). The activity exhibited by the pyrimidopurinediones in this model of chroni...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00125a029
更新日期：1989-05-01 00:00:00
abstract：:A series of analogues of the dipeptide sweetener L-aspartyl-L-phenylalanine methyl ester having hydroxy and/or methoxy substitution on the aromatic ring was synthesized and tasted. The introduction of a methoxy group in the para position of the aromatic ring of the peptide sweetener is crucial to the reduction or dest...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00178a013
更新日期：1980-04-01 00:00:00
abstract：:Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00401a014
更新日期：1988-06-01 00:00:00
abstract：:A molecular model of the human A(2B) adenosine receptor containing seven transmembrane alpha helices connected by three intracellular and three extracellular hydrophilic loops had been constructed. A molecular docking of seven structurally diverse xanthine antagonists of the A(2B) receptor was performed, and the diffe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049418o
更新日期：2005-11-03 00:00:00
abstract：:Peptidoaminobenzophenones (1), terminal N-substituted peptidoaminobenzophenones (14), and acylglycylaminobenzophenones (16) were prepared as a novel series of ring-opened derivatives of 1,4-benzodiazepine. Z-Gly- and Z-Ala-N-methylaminobenzophenones (4) were treated with HBr-HOAc to give Gly- and Ala-N-methylaminobenz...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00133a006
更新日期：1981-01-01 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
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01679
更新日期：2016-04-14 00:00:00
abstract：:Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101334y
更新日期：2011-04-28 00:00:00
abstract：:A molecular model of the alpha(IIb)beta(3) integrin has been developed utilizing (i). the crystal structure of alpha(v)beta(3), (ii). homology model of the alpha(IIb) subdomain, and (iii). the docking of alpha(IIb)beta(3)/alpha(v)beta(3) dual and selective inhibitors into the putative binding sites of alpha(IIb)beta(3...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030146j
更新日期：2003-12-04 00:00:00
abstract：:A series of novel 3-quinolinecarboxylic acid derivatives have been prepared and their antibacterial activity evaluated. These derivatives are characterized by fluorine attached to the 6-position and substituted amino groups appended to the 1- and 7-positions. Structure-activity relationship studies indicate that antib...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00375a003
更新日期：1984-09-01 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
pub_type： 杂志文章
doi：10.1021/jm00080a018
更新日期：1992-01-24 00:00:00
abstract：:Since the Z isomer of chlorprothixene (1) is far more active than its E counterpart, it was of interest to develop a stereoselective synthesis for this class of compounds. Insertion of a benzenesulfonamido group at the peri position of a chlorprothixene precursor did affect the stereochemistry of side-chain olefin for...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00145a005
更新日期：1985-07-01 00:00:00
abstract：:Seven 1,2-dihydroxy-1,2-dihydroacronycine and 1,2-dihydroxy-1,2-dihydro-6-demethoxyacronycine esters and diesters were synthesized via osmic oxidation of acronycine or 6-demethoxyacronycine followed by acylation. The 6-demethoxyacronycine derivatives were found to be inactive, whereas in contrast, all of the acronycin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9602975
更新日期：1996-11-22 00:00:00
abstract：:The preparation of a series of indole N-acyl and N-carbamic esters of (+/-)-alpha-5-[1-(indol-3-yl)ethyl]-2-methylamino-delta2-thiazolin-4-one (1) is reported. These derivatives were synthesized as potential water-soluble precursors of the antiviral thiazolinone 1, for evaluation by intranasal administration against i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00188a013
更新日期：1979-02-01 00:00:00
abstract：:The 5-fluoro and 8-fluoro analogues of trimetoquinol, TMQ, have been synthesized and evaluated for beta 2- and beta 1-adrenoceptor activity in guinea pig trachea and atria, respectively. The fluoro analogues of TMQ maintained potent beta 2-adrenoceptor agonist activity but had reduced beta 1-adrenoceptor agonist activ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00384a015
更新日期：1987-01-01 00:00:00
abstract：:The synthesis and biological evaluation of a series of 2-substituted 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), the only benzodiazepine that acts simultaneously as a kappa-opioid agonist and a cholecystokinin-A (CCK-A) antagonist, are reported. The radioligand binding models used in these stu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950423p
更新日期：1996-02-16 00:00:00
abstract：:Colony stimulation factor-1 receptor (CSF-1R), which is also known as FMS kinase, plays an important role in initiating inflammatory, cancer, and bone disorders when it is overstimulated by its ligand, CSF-1. Innate immunity, as well as macrophage differentiation and survival, are regulated by the stimulation of the C...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.7b00873
更新日期：2018-07-12 00:00:00
abstract：:The pharmaceutical industry has recognized that many drug-like molecules can self-aggregate in aqueous media and have physicochemical properties that skew experimental results and decisions. Herein, we introduce the use of a simple NMR strategy for detecting the formation of aggregates using dilution experiments that ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400535b
更新日期：2013-06-27 00:00:00
abstract：:Recent studies have indicated several therapeutic applications for delta opioid agonists and antagonists. To exploit the therapeutic potential of delta opioids developing a structural basis for the activity of ligands at the delta opioid receptor is essential. The conformationally sampled pharmacophore (CSP) method (B...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0612463
更新日期：2007-04-19 00:00:00
abstract：:Derivatives of 4-aryl-4-(dimethylamino)cyclohexan-1-ones substituted by m-hydroxy groups were obtained by using as a key reaction the displacement of cyanide from the alpha-aminonitrile of 1,4-cyclohexanedione ketal, with the THP ether of m-hydroxyphenylmagnesium bromide. A number of the products show narcotic antagon...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00135a019
更新日期：1981-03-01 00:00:00
abstract：:A series of analogues of 4,5-bis(((N-methylcarbamoyl)oxy)methyl)-1-methyl-2-(methylthio)-im idazole (1, carmethizole) were synthesized. The chemical reactivities of the analogues (as electrophiles) were evaluated and related to the antitumor activity (in vivo and in vitro). Changes in the alkylthio moiety had a signif...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00075a017
更新日期：1993-11-12 00:00:00
abstract：:Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases and decrease beta-amyloid (Abeta) levels by complexation of redox-active metals, respectively. In this work, novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100329q
更新日期：2010-07-08 00:00:00
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
更新日期：2001-08-02 00:00:00
abstract：:The 5-HT(6) receptor (5-HT(6)R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT(6)R antagonists to improve off-target selectivity compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the N'-(sulfon...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200466r
更新日期：2011-10-27 00:00:00
abstract：:cis-4-Hydroperoxycyclophosphamide (5) undergoes facile reaction with aqueous phosphate or Tris buffers at pH 7-8 and 30 degrees C. The kinetics of 5 are complex, and the trans-4-hydroperoxy isomer 6 is produced and subsequently disappears over the course of the reaction. Addition of hydrogen peroxide to the reaction m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00370a009
更新日期：1984-04-01 00:00:00
abstract：:An efficient and general method has been developed for fluorine-18 labeling of beta-blockers that possess the propanolamine moiety. A new synthetically versatile intermediate, 3-(1-(benzyloxy)propan-2-yl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (13), was prepared and can be conjugated to any phenoxy core....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800227h
更新日期：2008-08-28 00:00:00
abstract：:Oxadiazoles, like the benzoyl group in a series of imidazo[1,2-a]pyrimidines, have been found to be metabolically stable alternatives to ester groups in benzodiazepine-receptor ligands. This change has lead to a number of compounds which bind to the receptors and which exhibit potent agonist activity in a food-motivat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00111a021
更新日期：1991-07-01 00:00:00
abstract：:A series of 1-H-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure-activity-relationship study illustrates that the incorporation of a pyrimidine-fused heterocycle at position 4 of the pyrazole is critical f...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01261
更新日期：2018-02-22 00:00:00
abstract：:Recently, we have demonstrated that N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652) (1) adopts a bitopic pose at one protomer of a dopamine D2 receptor (D2R) dimer to negatively modulate the binding of dopamine at the other protomer. The 1H-indole-2-carboxa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00585
更新日期：2015-09-10 00:00:00
