Discovery of a novel and potent class of anti-HIV-1 maturation inhibitors with improved virology profile against gag polymorphisms.

A new class of betulin-derived α-keto amides was identified as HIV-1 maturation inhibitors. Through lead optimization, GSK8999 was identified with IC50 values of 17nM, 23nM, 25nM, and 8nM for wild type, Q369H, V370A, and T371A respectively. When tested in a panel of 62 HIV-1 isolates covering a diversity of CA-SP1 genotypes including A, AE, B, C, and G using a PBMC based assay, GSK8999 was potent against 57 of 62 isolates demonstrating an improvement over the first generation maturation inhibitor BVM. The data disclosed here also demonstrated that the new α-keto amide GSK8999 has a mechanism of action consistent with inhibition of the proteolytic cleavage of CA-SP1.

The design of 8-hydroxyquinoline tetracyclic lactams as HIV-1 integrase strand transfer inhibitors.

A novel series of HIV-1 integrase strand transfer inhibitors were designed using the venerable two-metal binding pharmacophore model and incorporating structural elements from two different literature scaffolds. This manuscript describes a number of 8-hydroxyquinoline tetracyclic lactams with exceptional antiviral activity against HIV-1 and little loss of potency against the IN signature resistance mutations Q148K and G140S/Q148H.

Synthesis and Biological Evaluation of Macrocyclized Betulin Derivatives as a Novel Class of Anti-HIV-1 Maturation Inhibitors.

A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, and it occupies a unique chemical space in drug discovery. However, the synthetic challenge to access this structural class is high and hinders the exploration of macrocycles. In this study, efficient synthetic routes to macrocyclized betulin derivatives have been established. The macrocycle containing compounds showed equal potency compared to bevirimat in multiple HIV-1 antiviral assays. The synthesis and biological evaluation of this novel series of HIV-1 maturation inhibitors will be discussed.

In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor.

S/GSK1349572 is a next-generation HIV integrase (IN) inhibitor designed to deliver potent antiviral activity with a low-milligram once-daily dose requiring no pharmacokinetic (PK) booster. In addition, S/GSK1349572 demonstrates activity against clinically relevant IN mutant viruses and has potential for a high genetic barrier to resistance. S/GSK1349572 is a two-metal-binding HIV integrase strand transfer inhibitor whose mechanism of action was established through in vitro integrase enzyme assays, resistance passage experiments, activity against viral strains resistant to other classes of anti-HIV agents, and mechanistic cellular assays. In a variety of cellular antiviral assays, S/GSK1349572 inhibited HIV replication with low-nanomolar or subnanomolar potency and with a selectivity index of 9,400. The protein-adjusted half-maximal effective concentration (PA-EC(50)) extrapolated to 100% human serum was 38 nM. When virus was passaged in the presence of S/GSK1349572, highly resistant mutants were not selected, but mutations that effected a low fold change (FC) in the EC(50) (up to 4.1 fold) were identified in the vicinity of the integrase active site. S/GSK1349572 demonstrated activity against site-directed molecular clones containing the raltegravir-resistant signature mutations Y143R, Q148K, N155H, and G140S/Q148H (FCs, 1.4, 1.1, 1.2, and 2.6, respectively), while these mutants led to a high FC in the EC(50) of raltegravir (11- to >130-fold). Either additive or synergistic effects were observed when S/GSK1349572 was tested in combination with representative approved antiretroviral agents; no antagonistic effects were seen. These findings demonstrate that S/GSK1349572 would be classified as a next-generation drug in the integrase inhibitor class, with a resistance profile markedly different from that of first-generation integrase inhibitors.

Laparoscopic and open partial nephrectomy: frequency and long-term follow-up of postoperative collections.

PURPOSE: To compare imaging findings between laproscopic and open partial nephrectomy at 6 months after surgery and to follow the evolution of the findings over time. MATERIALS AND METHODS: This HIPAA-compliant retrospective study had institutional review board approval and consent was waived. A surgical database was cross-referenced with an imaging database to identify patients who underwent partial nephrectomy and computed tomographic and/or magnetic resonance imaging within 6 months of surgery. Fifty-eight patients (mean age, 61 years; range, 34-78 years; 21 women, 37 men) underwent 62 partial nephrectomies (laparoscopic, 31; open, 31) to remove 68 masses. Two radiologists in consensus reviewed images obtained between 10 days and 72 months (mean, 28 months) after surgery. Preoperative mass size and location and postoperative kidney orientation, fat stranding, parenchymal defect, collection (including size, location, and appearance), and other complications were recorded. Relative incidence of postoperative imaging findings, demographics, and initial imaging findings of both groups were statistically assessed by using Student t and chi(2) tests corrected for multiple comparisons. RESULTS: Common imaging findings following surgery included kidney displacement (48% [30 of 62]), perinephric fat stranding (93% [63 of 68]), parenchymal defect (74% [50 of 68]), and a non-fat-containing postoperative collection 75%, with significantly more posterior renal displacement (P < .01) and a trend toward more persistent fat stranding in the open surgery group. Fifty-one collections were identified in 74% (43 of 58) of patients, with significantly more collections in the laparoscopic (90% [27 of 30] vs 55% [16 of 29]; P < .05). The proportion of resolved collections increased over time, with significantly more resolving in the open group within 24 months of surgery (P < .05). Development or resolution of a collection was not dependent on age, sex, preoperative lesion size, or location (P > .05). CONCLUSION: Prevalence of findings 2-3 years after partial nephrectomy depends on the surgical approach. After laparoscopic partial nephrectomy, collections are more frequently detected on images and may take longer to resolve than following an open approach.

Substituted tetrahydro-beta-carbolines as potential agents for the treatment of human papillomavirus infection.

The identification and optimization of a series of substituted tetrahydro-beta-carbolines with potent activity against human papillomavirus is described. Structure-activity studies focused on the substitution pattern and chirality of the beta-carboline ring system are discussed. Optimization of these parameters led to compounds with antiviral activities in the low nanomolar range.

Tetrahydrocarbazole amides with potent activity against human papillomaviruses.

Synthesis of a series of tetrahydrocarbazole amides with potent activity against human papillomaviruses is described. Synthetic approaches allowing for variation of the substitution pattern of the tetrahydrocarbazole and the amide are outlined and resulting changes in antiviral activity and certain developability parameters are highlighted. Several compounds with in vitro antiviral activity (W12 antiviral assay) in the single digit nanomolar range were identified and N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-pyridinecarboxamide was selected for further evaluation.

Substituted tetrahydrocarbazoles with potent activity against human papillomaviruses.

The synthesis and SAR of a series of substituted 1-aminotetrahydrocarbazoles with potent activity against human papillomaviruses are described. Synthetic approaches allowing for variation of the substitution pattern of the tetrahydrocarbazole are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity (W12 antiviral assay) in the low nanomolar range were identified and (1R)-6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazole-1-amine was selected for further evaluation.

MRI findings associated with distal tibiofibular syndesmosis injury.

OBJECTIVE: Our objective was to describe the MRI findings associated with acute and chronic distal tibiofibular syndesmosis injury. MATERIALS AND METHODS: Ninety-four 1.5-T MRIs of ankles of 90 individuals with histories of severe sprain were assessed by two musculoskeletal radiologists for syndesmosis injury (acute, edema of the syndesmosis; chronic, disruption or thickening of the syndesmosis without edema). We examined associated MRI findings, including anterior talofibular ligament injury (scar, chronic injury; edema, acute injury), bone bruise, osteochondral lesion, tibiofibular joint congruity, tibiofibular recess height, and osteoarthritis. The Fisher's exact test and analysis of variance test were used to evaluate the significance of the associations. RESULTS: In 94 ankles, syndesmosis injury was seen in 63% (n = 59; 23 acute; 36 chronic). Anterior talofibular ligament injury (acute or chronic) was seen on MRIs in 74% (n = 70; 49 with syndesmosis injury; 21 without; p = 0.03). Bone bruises were present in 24% (n = 23; 18/23 acute; 4/36 chronic; 4/35 no injury; p < 0.0001). Of these, talar dome osteochondral lesions were present in 28% (n = 26; 11/23 acute; 14/36 chronic; 1/35 no injury; p = 0.0001; 13 medial; 13 lateral). The tibiofibular joint was incongruent in 33% (n = 31; 6/23 acute; 21/36 chronic; 4/35 no injury; p < 0.0001). The tibiofibular recess (mean +/- SD) was 1.2 +/- 0.92 cm in acute cases, 1.4 +/- 0.57 cm in chronic cases, and 0.54 +/- 0.68 cm in cases with no syndesmosis injury (p < 0.0001). Osteoarthritis was present in 10% (n = 9; 1/23 acute; 7/36 chronic; 1/35 no injury; p = 0.06). CONCLUSION: Injury to the distal tibiofibular syndesmosis has a significant association with a number of secondary findings on MRI, including anterior talofibular ligament injury, bone bruises, osteochondral lesions, tibiofibular joint congruity, and height of the tibiofibular recess.