Thomas Joseph Caggiano

The design, synthesis and physical chemical properties of novel human vasopressin V2-receptor antagonists optimized for parenteral delivery.

Ionizable groups were introduced onto the 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine scaffold of the vasopressin V2-antagonist WAY-VPA-985 in the search for molecules optimized for parenteral formulation. The synthesis and structure activity relationships (SAR) are presented together with solubility data in a model parenteral system. The amine, WAY-140288 (4f), was chosen for further development. p6

The activity of pathway-selective estrogen receptor ligands in experimental septic shock.

Estrogen receptors (ER) are widely expressed in multiple genital and nongenital tissues. Upon engagement of these receptors, multiple genes are affected in target tissues via estrogen response elements. Nonsteroidal pathway-selective ER ligands have recently been identified that inhibit NF-κB transcriptional activity and are devoid of conventional estrogenic activities on genital tissues. These pathway-selective ligands are potent anti-inflammatory agents in vivo and may prove to be of therapeutic utility in systemic inflammatory states. These pathway-selective ER ligands were tested in the murine listeriosis model, the neutropenic rat model, and the mouse cecal ligation and puncture model. WAY-204688 did not have any significant activity after systemic infection by Listeria monocytogenes. In the neutropenic rat model, WAY-204688 provided a significant survival benefit against an otherwise lethal challenge of Pseudomonas aeruginosa 12.4.4 compared with the control group (88% versus 25% survival; P < 0.05). Preservation of mucosal weight and prevention of histopathologic changes were observed with the administration of WAY-204688. Similar findings were observed in a cecal ligation and puncture model with WAY-204688 and a related compound WAY-169916. These results indicate that oral administration of these pathway-selective ER ligands preserved gastrointestinal barrier function and improve outcome in experimental models of systemic infection and inflammation. These agents may prove to be useful clinically as a novel treatment strategy for severe sepsis.

SYNTHESIS AND BIOACTIVITY OF PHOTOLABILE SIROLIMUS (RAPAMYCIN) ANALOGS

Several photolabile sirolimus analogs have been synthesized. All ot the compounds showed an antiproliferative effect in a mitogen-induced thymocyte proliferation assay. Compounds 3 and 4 were shown to be equipotent to sirolimus in a murine skin allograft model; they should thus be useful for investigating the in vivo details of the signal transduction pathway(s) modulated by sirolimus. The immunosuppressive effect of analogs 3–5 is corroborated by their ability, as part of an FKBP12 complex, to bind a sirolimus effector protein (SEP).

Synthesis and structure―activity relationship of a novel series of heterocyclic sulfonamide γ-secretase inhibitors

gamma-Secretase inhibitors have been shown to reduce the production of beta-amyloid, a component of the plaques that are found in brains of patients with Alzheimers disease. A novel series of heterocyclic sulfonamide gamma-secretase inhibitors that reduce beta-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative gamma-secretase substrate.

Chapter 21. Recent Advances in Bone Metabolism and Osteoporosis Research

Publisher Summary Although the term “osteoporosis” (OP) is frequently used in reference to the process of abnormally accelerated bone loss (osteopenia), particularly that associated with the onset of menopause, it is, in fact, a heterogeneous disorder clinically defined as a predisposition to bone fracture. It is the pathological end result of multiple causes and risk factors that include peak bone mass prior to the onset of aging-related bone loss and, in women, its exacerbation by the loss of ovarian hormonal support. There has been an exponential growth in the fundamental knowledge of bone metabolism and how defects in this system are reflected in disorders, such as OP, Pagets disease, and osteomalacia. This chapter discusses some of the new developments in bone research at both the basic and clinical levels. The chapter explains bone metabolism with mechanistic insights that involves growth factors, cytokines, noncollagenous bone protein, bone cell estrogen receptor, proton pump, calcitonin, and superoxide. Clinical developments include current therapies and recent therapies on osteoporosis diagnosis and treatment, hormone replacement, bisphosphonates (BP), calcitonin, and thiazide therapies. Advancements in clinical and preclinical research have resulted in tests for the identification of antiresorptive agents, bone formation inducing agents, bisphosphonate modes of action, enzyme inhibitors, prostaglandins, and other agents.

Chapter 17 Medicinal Chemistry Opportunities in Bone Metabolism and Osteoporosis

Publisher Summary Recent research has aided in a substantial increase in the knowledge of basic bone metabolism. Bone is a dynamic tissue that continuously undergoes remodeling. Approximately 10% of cortical bone, the dense, mineral-rich bone that comprises the shafts of long bones, and 20%-40% of the trabecular bone, cancellous bone found in the interior of vertebrae and in the medullary space of long bones, is remodeled each year in the healthy adult. In this process, multinuclear osteoclasts resorb bone releasing mineral and matrix peptide constituents. This resorption is linked to a rebuilding process, in which osteoblasts replace eroded bone tissue. Osteoporosis (OP) is a debilitating progressive loss of bone mineral that ultimately manifests itself in elevated fracture rates, generally among those over age 45. OP is most prevalent among postmenopausal women, but affects both the sexes. Traditionally, modulation of the endocrine system has been the preferred approach to the management of OP. This chapter explains the topics in preclinical bone metabolism research as well as significant new developments in clinical management of OP. Practical in vitro and in vivo models are now available to serve as a basis for the study of synthetic mediators of bone mechanism. Thus, the development of novel therapeutic approaches to the clinical management of disease represents a significant opportunity in medicinal chemistry.