Larry Murphy

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Recent evidence has suggested that arachidonic acid (AA) may be an important signaling molecule in cardiac excitation-contraction coupling. We previously showed that AA and endothelin-1 (ET) inhibit distinct K+ channels via protein kinase C-dependent pathways in rat ventricular myocytes. In addition, we demonstrated that Ca2+ transients in populations of(More)
Stimulation of insulin secretion is accompanied by changes in the phosphorylation state of several islet polypeptides. Protein (de)phosphorylation is mediated by the action of protein kinases and phosphoprotein phosphatases. In this study we have investigated expression of phospho-serine/threonine phosphatases (PPs) in rat islets of Langerhans and studied(More)
We describe the in vitro evaluation and crystallographic analysis of a new class of potent and selective, non-amino acid-based, small-molecule thrombin inhibitors, exemplified by 14. This class of achiral inhibitors lacks an amide-based backbone, exhibits nM inhibition of thrombin, and is selective for thrombin. Compound 14 does not interact with the(More)
Although thrombin has been extensively researched with many examples of potent and selective inhibitors, the key characteristics of oral bioavailability and long half-life have been elusive. We report here a novel series non-peptidic phenyl-based, highly potent, highly selective and orally bioavailable thrombin inhibitors using oxyguanidines as(More)
We describe a new class of potent, non-amide-based small molecule thrombin inhibitors in which an amidinohydrazone is used as a guanidine bioisostere on a non-peptide scaffold. Compound 4 exhibits nM inhibition of thrombin, is selective for thrombin, and shows 60 and 23% bioavailability in rabbits and dogs, respectively. Crystallographic analysis of 4 bound(More)
We expand the structural requirements and structure-activity relationship of a novel class of non-peptidic aryl-based thrombin inhibitors through exploration of the S1 specificity pocket of thrombin using flexible and constrained amidines. The most active compound of this class is 11 with Ki = 69 nM, which is ca. 15-fold less potent than constrained(More)
The structure activity relationships of a novel series of non-amide-based thrombin inhibitors are described. Exploration of the P2 and the aryl binding region for this series has identified optimal groups for achieving nanomolar potency. The binding modes of these optimal groups have been confirmed by X-ray structural analysis.
In-depth structured interviews were conducted with spokespeople for 176 inner-city churches regarding perceptions of existing community problems, number of currently offered church-based social and health programs, and potential interest in church sponsorship of new maternal and child health programs. The sample of respondents represented 78% of the 227(More)
Testicular feminized (Tfm) mice are totally insensitive to androgen and may be used to study the role of the androgen receptor in normal development and function. We have examined testicular and Leydig cell steroidogenesis in Tfm mice. Serum bioactive LH was high in Tfm mice but serum testosterone was low and this was associated with a severe reduction in(More)
The testicular feminized (Tfm) mouse lacks functional androgen receptors and develops with a female external phenotype and internal testes. The testes of these animals contain normal, or close to normal, numbers of Leydig cells but secrete very low amounts of androgen due to a lack of 17 alpha-hydroxylase activity. To determine whether this loss of activity(More)