Half-Life Extension of BMP1/TLL Metalloproteinase Inhibitors Using Small-Molecule Human Serum Albumin Binders.

Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer half-lives are highly desirable. One of the most promising approaches to extend the half-life of drugs is conjugation to human serum albumin (HSA).

Cardioprotection by systemic dosing of thymosin beta four following ischemic myocardial injury.

Thymosin beta 4 (Tβ4) was previously shown to reduce infarct size and improve contractile performance in chronic myocardial ischemic injury via two phases of action: an acute phase, just after injury, when Tβ4 preserves ischemic myocardium via antiapoptotic or anti-inflammatory mechanisms; and a chronic phase, when Tβ4 activates the growth of vascular or cardiac progenitor cells. In order to differentiate between the effects of Tβ4 during the acute and during the chronic phases, and also in order to obtain detailed hemodynamic and biomarker data on the effects of Tβ4 treatment suitable for use in clinical studies, we tested Tβ4 in a rat model of chronic myocardial ischemia using two dosing regimens: short term dosing (Tβ4 administered only during the first 3 days following injury), and long term dosing (Tβ4 administered during the first 3 days following injury and also every third day until the end of the study). Tβ4 administered throughout the study reduced infarct size and resulted in significant improvements in hemodynamic performance; however, chamber volumes and ejection fractions were not significantly improved.

Mechano-growth factor peptide, the COOH terminus of unprocessed insulin-like growth factor 1, has no apparent effect on myoblasts or primary muscle stem cells.

A splice form of IGF-1, IGF-1Eb, is upregulated after exercise or injury. Physiological responses have been ascribed to the 24-amino acid COOH-terminal peptide that is cleaved from the NH3-terminal 70-amino acid mature IGF-1 protein. This COOH-terminal peptide was termed "mechano-growth factor" (MGF).

Human-induced pluripotent stem cell-derived cardiomyocytes exhibit temporal changes in phenotype.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) have been recently derived and are used for basic research, cardiotoxicity assessment, and phenotypic screening. However, the hiPS-CM phenotype is dependent on their derivation, age, and culture conditions, and there is disagreement as to what constitutes a functional hiPS-CM. The aim of the present study is to characterize the temporal changes in hiPS-CM phenotype by examining five determinants of cardiomyocyte function: gene expression, ion channel functionality, calcium cycling, metabolic activity, and responsiveness to cardioactive compounds.

Chronic inhibition of hypoxia-inducible factor prolyl 4-hydroxylase improves ventricular performance, remodeling, and vascularity after myocardial infarction in the rat.

Background: Hypoxia inducible factors (HIFs) are transcription factors that are regulated by HIF-prolyl 4-hydroxylases (PHDs) in response to changes in oxygen tension. Once activated, HIFs play an important role in angiogenesis, erythropoiesis, proliferation, cell survival, inflammation, and energy metabolism. We hypothesized that GSK360A, a novel orally active HIF-PHD inhibitor, could facilitate local and systemic HIF-1 alpha signaling and protect the failing heart after myocardial infarction (MI).

Cathepsin S expression is up-regulated following balloon angioplasty in the hypercholesterolemic rabbit.

Objective: Neointimal development following balloon angioplasty involves many factors including smooth muscle cell (SMC) migration and proliferation and extracellular matrix (ECM) remodeling. Further, in hypercholesterolemic (HC) conditions, there is an influx of macrophage foam cells (FCs) into the restenotic lesion, which also involves degradation of the basement membrane and surrounding ECM. The ECM remodeling that occurs during restenosis has been shown to be mediated by various proteases.

Potent quinoxaline-based inhibitors of PDGF receptor tyrosine kinase activity. Part 2: the synthesis and biological activities of RPR127963 an orally bioavailable inhibitor.

RPR127963 demonstrates an excellent pharmacokinetic profile in several species and was found to be efficacious in the prevention of restenosis in a Yucatan mini-pig model upon oral administration of 1-5 mg/kg. The in vitro selectivity profile and SAR of the highly optimized PDGF-R tyrosine kinase inhibitor are highlighted.

Potent quinoxaline-based inhibitors of PDGF receptor tyrosine kinase activity. Part 1: SAR exploration and effective bioisosteric replacement of a phenyl substituent.

Novel substituted 2-anilino- and 2-cycloalkylaminoquinoxalines have been found to be useful and selective inhibitors of PDGF-R autophosphorylation. Replacement of an anilino-substituent with substituted cyclohexylamino- or norbornylamino substituents led to significant improvements in the pharmacokinetic profile of these analogues.

Stent-induced restenosis in the swine coronary artery is inhibited by a platelet-derived growth factor receptor tyrosine kinase inhibitor, TKI963.

Activities of vascular smooth muscle cells (SMCs) such as proliferation, migration, and matrix production contribute to restenosis following clinical interventions of angioplasty and stent placement. Because activation of platelet-derived growth factor (PDGF)-receptor tyrosine kinase (PDGFr-TK) influences these processes and promotes restenosis, TKI963, an inhibitor of the PDGFr-TK was discovered, and its efficacy was evaluated in blocking stent-induced restenosis as analyzed by intravascular ultrasound (IVUS). TKI963, a low-molecular-weight compound, inhibited the cell-free PDGFbetar-TK with a K(i) value of 56 +/- 14 nM.