3D finite element modeling of pelvic organ prolapse.

OBJECTIVES: The purpose of this study is to develop a validated 3D finite element model of the pelvic floor system which can offer insights into the mechanics of anterior vaginal wall prolapse and have the ability to assess biomedical device treatment methods. The finite element results should accurately mimic the clinical findings of prolapse due to intra-abdominal pressure (IAP) and soft tissues impairment conditions. METHODS: A 3D model of pelvic system was created in Creo Parametric 2.0 based on MRI Images, which included uterus, cervix, vagina, cardinal ligaments, uterosacral ligaments, and a simplified levator plate and rectum. The geometrical model was imported into ANSYS Workbench 14.5. Mechanical properties of soft tissues were based on experimental data of tensile test results from current literature. Studies were conducted for IAP loadings on the vaginal wall and uterus, increasing from lowest to extreme values. RESULTS: Anterior vaginal wall collapse occurred at an IAP value corresponding to maximal valsalva and showed similar collapsed shape as clinical findings. Prolapse conditions exhibited high sensitivity to vaginal wall stiffness, whereas healthy tissues was found to support the vagina against prolapse. Ligament impairment was found to have only a secondary effect on prolapse.

Discovery of an oral respiratory syncytial virus (RSV) fusion inhibitor (GS-5806) and clinical proof of concept in a human RSV challenge study.

GS-5806 is a novel, orally bioavailable RSV fusion inhibitor discovered following a lead optimization campaign on a screening hit. The oral absorption properties were optimized by converting to the pyrazolo[1,5-a]-pyrimidine heterocycle, while potency, metabolic, and physicochemical properties were optimized by introducing the para-chloro and aminopyrrolidine groups. A mean EC50 = 0.43 nM was found toward a panel of 75 RSV A and B clinical isolates and dose-dependent antiviral efficacy in the cotton rat model of RSV infection. Oral bioavailability in preclinical species ranged from 46 to 100%, with evidence of efficient penetration into lung tissue. In healthy human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a mean 4.2 log10 reduction in peak viral load and a significant reduction in disease severity compared to placebo. In conclusion, a potent, once daily, oral RSV fusion inhibitor with the potential to treat RSV infection in infants and adults is reported.

Optimization of Pharmacokinetics through Manipulation of Physicochemical Properties in a Series of HCV Inhibitors.

A novel series of HCV replication inhibitors based on a pyrido[3,2-d]pyrimidine core were optimized for pharmacokinetics (PK) in rats. Several associations between physicochemical properties and PK were identified and exploited to guide the design of compounds. In addition, a simple new metric that may aid in the prediction of bioavailability for compounds with higher polar surface area is described (3*HBD-cLogP).

N1-Alkyl pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase.

A series of N1-alkyl pyrimidinediones were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our efforts identified compound 10b, which represents the lead compound in this series with pharmacokinetics and antiviral potency that may support once-daily dosing.

N1-Heterocyclic pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase.

A series of N1-heterocyclic pyrimidinediones were extensively evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Inhibitor 1 is active against NNRTI-resistant viruses including RT mutant K103N. The co-crystal structure of inhibitor 1 with HIV-1 RT revealed that H-bonds are formed with K101 and K103. Efforts to improve the suboptimal pharmacokinetic profile of 1 resulted in the discovery of compound 13, which represents the lead compound in this series with improved pharmacokinetics and similar potency as inhibitor 1.