The discovery and structure-activity relationships of pyrano[3,4-b]indole based inhibitors of hepatitis C virus NS5B polymerase.

We describe the structure-activity relationship of the C1-group of pyrano[3,4-b]indole based inhibitors of HCV NS5B polymerase. Further exploration of the allosteric binding site led to the discovery of the significantly more potent compound 12.

Phenyltriazolinones as potent factor Xa inhibitors.

We have discovered that phenyltriazolinone is a novel and potent P1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S1 binding pocket which is larger in size to accommodate the phenyltriazolinone P1 substrate.

1-[3-Aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa.

Attempts to further optimize the pyrazole factor Xa inhibitors centered on masking the aryl aniline P4 moiety. Scaffold optimization resulted in the identification of a novel bicyclic pyrazolo-pyridinone scaffold which retained fXa potency. The novel bicyclic scaffold preserved all binding interactions observed with the monocyclic counterpart and importantly the carboxamido moiety was integrated within the scaffold making it less susceptible to hydrolysis.

Tetrahydrobenzothiophene inhibitors of hepatitis C virus NS5B polymerase.

A novel series of selective HCV NS5B RNA dependent RNA polymerase inhibitors has been disclosed. These compounds contain an appropriately substituted tetrahydrobenzothiophene scaffold. This communication will detail the SAR and activities of this series.

Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa.

Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation.

Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors.

Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report the design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity.

Arabinogalactan-coated superparamagnetic iron oxide: effect of particle size in liver MRI.

Objective: We evaluated the effect of particle size on MR contrast-enhancing properties of arabinogalactan-coated superparamagnetic iron oxide (AG-SPIO) in tumor-bearing rats.

Materials And Methods: T2*-weighted gradient-recalled echo MR studies were performed on rats with surgically implanted liver tumors before and after AG-SPIO administration. Contrast-to-noise ratio (CNR) and percent contrast enhancement (PCE) were calculated for animals given small (15.

Preclinical evaluation of manganese carbonate particles for magnetic resonance imaging of the liver.

Rationale And Objectives: We characterized the physical, biological, and imaging properties of a manganese (Mn) carbonate particle suspension, a contrast agent for hepatic magnetic resonance (MR) imaging.

Methods: Mn carbonate suspensions were produced by controlled precipitation and characterized using light microscopy, transmission electron microscopy, and in vitro relaxivity studies. Efficacy of the agent was studied in normal and tumor-bearing rats using T1-weighted MR imaging.

Is there a role for diskography in the era of magnetic resonance imaging? Prospective correlation and quantitative analysis of computed tomography-diskography, magnetic resonance imaging, and surgical findings.

We herein report the results of a prospective study to define the role of diskography in the diagnosis of low back pain in an emerging era of magnetic resonance imaging (MRI). The study involved 32 patients (78 disks) with a clinical diagnosis of lumbar disk herniation; all were studied by computed tomography-diskography (CT-D), and 25 (51 disks) were also examined using MRI. The disks were graded on these studies according to a staging scheme modified from Modic.

Anatomic variation of the corpus callosum in persons with gender dysphoria.

Previous postmortem anatomical studies have demonstrated differences between male and female in the size and shape of the splenium of the corpus callosum. The current study using the magnetic resonance imager compares the corpus callosum in 20 transsexuals and 40 controls to determine if the anatomic variance is related to anatomic sex or gender identity. No statistical differences were found in the cross-sectional areas of the entire corpus callosum, regardless of genetic sex or gender.

T-gamma-lymphoproliferative disorder arising in a background of autoimmune disease and terminating in plasma cell dyscrasia with primary amyloidosis.

T-gamma-lymphoproliferative disorder, a syndrome of T-cell lymphocytosis with neutropenia has been described in patients with various autoimmune disorders, especially rheumatoid arthritis. We report a case of T-gamma-lymphoproliferative disorder occurring in a 42-year-old white woman with a long history of dermatitis herpetiformis and subsequent development of Coomb's positive autoimmune hemolytic anemia and polymyositis. The peripheral blood lymphocytes showed the T-suppressor cell phenotype (CD2-, CD3-, CD8-, and CD4-).

Magnetic resonance imaging and neuropsychological findings in human immunodeficiency virus infection.

Neurobehavioral functioning and magnetic resonance imaging (MRI) were investigated in 25 patients with various Centers for Disease Control (CDC) stages of human immunodeficiency virus (HIV) infection and in a control group of seven normal subjects. Unequivocal slowing of information processing speed and cerebral atrophy were related to the stage of HIV infection, with patients in CDC group IV exhibiting the most abnormal findings. Slowing of response speed was directly related to the severity of cerebral atrophy.

Localization of auditory response sources using magnetoencephalography and magnetic resonance imaging.

Magnetoencephalography offers the possibility of localizing accurately and noninvasively the source of intracranial currents associated with normal and abnormal brain activity. The purpose of this study was to assess the validity and across-subject reliability of localization of cortical sources responding to ipsilateral and contralateral auditory stimulation. Magnetic evoked fields to both stimulation conditions were measured in eight consecutive normal subjects, and the cortical sources of these fields were estimated on the basis of these measurements.

Neurobehavioral and magnetic resonance imaging findings in two cases of decompression sickness.

Two divers underwent neurobehavioral examinations and magnetic resonance imaging (MRI) while hospitalized during the first 2 weeks after sustaining decompression sickness (DCS). Their neurologic findings included a Brown-Séquard Syndrome consistent with spinal cord lesion, and focal deficits consistent with cerebral lesion(s). MRI revealed subcortical white matter lesions in the brains of both divers, whereas no lesion of the spinal cord was demonstrated.

Magnetic resonance imaging in the assessment of revascularization in Kienbock's disease. A preliminary report.

A 25-year-old man with stage II Kienbock's disease of his left lunate underwent an initial period of immobilization. He was subsequently treated by ulnar lengthening, with a good outcome. Magnetic resonance imaging (MRI) was utilized to demonstrate the lack of improvement with cast immobilization and the revascularization that followed surgical treatment.

Dichotic listening and manual performance in relation to magnetic resonance imaging after closed head injury.

In order to investigate post-traumatic hemispheric disconnection effects, dichotic listening and intermanual tasks were administered to 69 patients who had sustained a closed head injury of varying severity. The manual tasks consisted of naming objects palpated in either hand, transfer of postures from one hand to the other and writing. Consistent with predictions, the degree of ear asymmetry in dichotic listening performance was directly related to the severity of the head injury as reflected by the degree of impaired consciousness.

Cerebral blood volume in a rat model of ischemia by MR imaging at 4.7 T.

Perturbation of the cerebral circulation by occlusion of the vertebral arteries and a carotid artery can be visualized by using MR imaging and the intravascular contrast agent Gd-DTPA complexed to albumin. This tracer consistently reduced the T1 relaxation time in the brain and blood. The difference between hemispheres was revealed by less T1 reduction in the occluded hemisphere and by an adjustment in the display contrast of images that revealed the territory of decreased perfusion.

Magnetic resonance imaging after closed head injury in children.

Magnetic resonance imaging (MRI) was performed in a series of 21 children and adolescents who had been hospitalized after sustaining closed head injuries of varying severity at least 6 months previously. Areas of high intensity in the parenchyma were present in 8 of the 11 severely injured patients, whereas MRI findings were normal in all 10 patients with mild-to-moderate head injuries. Lesions involving the subcortical white matter were confined to severely injured patients whose clinical features were compatible with diffuse axonal injury.

Relationship of depth of brain lesions to consciousness and outcome after closed head injury.

Magnetic resonance (MR) imaging was performed in 94 patients who sustained closed head injury of varying severity. Results of MR studies obtained after the intensive care phase of treatment disclosed that intracranial lesions were present in about 88% of the patients. Consistent with the centripetal model of progressive brain injury proposed in 1974 by Ommaya and Gennarelli, the depth of brain lesion was positively related to the degree and duration of impaired consciousness.

MR imaging of uterine cervical carcinoma.

We retrospectively analyzed the magnetic resonance (MR) imaging findings of 20 consecutive patients with primary untreated carcinoma of the cervix who underwent surgery and one patient who underwent percutaneous needle biopsy of enlarged pelvic lymph nodes. Most of the patients were clinical Stage IB. The clinical assessment of the parametria in these patients was more accurate than the MR assessment of the parametria (95 versus 79%).

MRI of cervical carcinoma.

MRI is useful for demonstrating enlarged retroperitoneal lymph nodes and for demonstrating the carcinoma mass in patients with carcinoma of the cervix. MRI evaluation of the parametria appears promising, but further studies are necessary to elucidate the optimal imaging parameters and to better define the overall accuracy of MRI compared to the clinical evaluation of the parametria.

MR imaging of mediastinal pseudocyst.

Magnetic resonance imaging of a mediastinal pseudocyst clearly demonstrated the entirely intrathoracic location of the pseudocyst.