Species comparison of compounds with known blood pressure effects in a vascular smooth muscle cell collagen contraction assay.

Introduction: There is a great need for new approaches early in drug discovery that have the potential to improve clinical translation of compound-mediated cardiovascular effects. Current approaches frequently rely on in vivo animal models or in vitro tissue bath preparations, both of which are low throughput and costly. An in vitro surrogate screen for blood pressure using primary human cells may serve as a higher throughput method to quickly select compounds void of this secondary pharmacology and potentially improve late-stage drug development outcomes.

Comparison of Toxicities among Different Bumped Kinase Inhibitor Analogs for Treatment of Cryptosporidiosis.

Recent advances on the development of bumped kinase inhibitors for treatment of cryptosporidiosis have focused on the 5-aminopyrazole-4-carboxamide scaffold, due to analogs that have less hERG inhibition, superior efficacy, and strong safety profiles. Three compounds, BKI-1770, -1841, and -1708, showed strong efficacy in C. parvum infected mice.

Disconnect between COX-2 selective inhibition and cardiovascular risk in preclinical models.

Introduction: Secondary pharmacology profiling is routinely applied in pharmaceutical drug discovery to investigate the pharmaceutical effects of a drug at molecular targets distinct from (off-target) the intended therapeutic molecular target (on-target). Data from a randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on VIOXX, rofecoxib) trial, raised significant concerns about COX-2 inhibition as a primary or secondary target, shaping the screening and decision-making processes of some pharmaceutical companies. COX-2 is often included in off-target screens due to cardiovascular (CV) safety concerns about secondary interactions with this target.

Tumor necrosis factor receptor superfamily members 1a and 1b contribute to exacerbation of atherosclerosis by Chlamydia pneumoniae in mice.

The host immune responses that mediate Chlamydia-induced chronic disease sequelae are incompletely understood. The role of TNF-α, TNF receptor 1 (TNFR1), and TNF receptor 2 (TNFR2), in Chlamydia pneumoniae (CPN)-induced atherosclerosis was studied using the high-fat diet-fed male C57BL/6J mouse model. Following intranasal CPN infection, TNF-α knockout (KO), TNFR1 KO, TNFR2 KO, and TNFR 1/2 double-knockout, displayed comparable serum anti-chlamydial antibody response, splenic antigen-specific cytokine response, and serum cholesterol profiles compared to wild type (WT) animals.

CD8+ T cells mediate Chlamydia pneumoniae-induced atherosclerosis in mice.

Chlamydia pneumoniae is a community-acquired bacterial pathogen that has been strongly associated with exacerbation of atherosclerosis. We evaluated the role of CD8(+) T cells in the C57BL/6J mouse model of C. pneumoniae-induced atherosclerosis.

Intranasal vaccination with Chlamydia pneumoniae induces cross-species immunity against genital Chlamydia muridarum challenge in mice.

Chlamydia trachomatis is the most common bacterial sexually transmitted disease in the world and specifically in the United States, with the highest incidence in age-groups 14-19 years. In a subset of females, the C. trachomatis genital infection leads to serious pathological sequelae including pelvic inflammatory disease, ectopic pregnancy, and infertility.