BACKGROUNDProducts of the arachidonic acid-metabolizing enzyme, 5-lipoxygenase, stimulate the growth of several cell types. Selective inhibitors of the enzyme, including SC41661A and MK886, reduce PC-3 prostate cell proliferation. With continued culture, cells die, but the mode of death, necrotic or nonnecrotic, has not been established.METHODSFlow cytometry, laddering after agarose electrophoresis of DNA from inhibitor-treated cells, and light and electron microscopy were employed to examine the type of death in PC-3 prostate cells cultured with either 5-lipoxygenase inhibitor.RESULTSThe inhibitors induced nonnecrotic, programmed cell death. SC41661A-treated cells exhibited "foamy," vacuolated cytoplasm and mitochondria with disrupted cristae and limiting membranes, while some cells contained numerous polysomes and extended hypertrophic Golgi and secretory cisternal networks. A proportion of the treated cells detached and the nuclei of these cells were characteristic of type 1 "apoptotic" programmed cell death. MK886, a 5-lipoxygenase-inhibitor with a different mechanism of action, induced nonnecrotic changes largely confined to the cytoplasm, most consistent with type 2 "autophagic" programmed cell death. In preliminary studies of mechanism, we demonstrated that PC-3 cells express mRNA for 5-lipoxygenase and for 5-lipoxygenase-activating protein. The less active inhibitor, SC45662 neither reduced proliferation nor induced DNA laddering. The antioxidant, N-acetyl-l-cysteine but not butylated hydroxy toluene or alpha tocopherol, partially reduced the inhibition of proliferation from SC41661A.CONCLUSIONSSC41661A and MK886 inhibit PC-3 cell proliferation and induce a form of type 1 or type 2 programmed cell death, respectively. PC-3 cells contain messenger RNA for 5-lipoxygenase and 5-lipoxygenase-activating proteins. Drug-induced changes included altered redox potential, inferred from the increased survival due to the antioxidant and glutathione precursor, N-acetyl-l-cysteine. PC-3 cells are an appropriate model for studying the mechanism responsible for 5-lipoxygenase inhibitor-induced cellular suicide.

01 Mar 1994·Biochemical PharmacologyQ2 · MEDICINE

Contrasting effects of two arachidonate 5-lipoxygenase inhibitors on formyl-methionyl-leucyl-phenylalanine (fMLP) and complement fragment 5a induced human neutrophil superoxide generation

Q2 · MEDICINE

Article

Author: Walter G. Smith ; Richard A. Partis ; Richard A. Mueller ; Akira Nakao ; Geralyn P. Kocan

SC-45662 and SC-41661A, selective arachidonate 5-lipoxygenase (5-LO) inhibitors, had markedly different effects on formyl-methionyl-leucyl-phenylalanine (fMLP) and complement fragment 5a (C5a) induced superoxide release from human neutrophils (PMNs). SC-45662 inhibited superoxide generation induced by fMLP and C5a with IC50 values of 12 and 5 microM, respectively. Furthermore, SC-45662 was capable of inhibiting fMLP and C5a induced superoxide release in PMNs primed with bacterial lipopolysaccharide, tumor necrosis factor-alpha and other priming agents. SC-41661A, a compound from the same chemical series as SC-45662, did not inhibit or induce superoxide generation, but instead primed PMNs for fMLP and C5a induced superoxide generation. The induced superoxide release was concentration dependently enhanced 2 to 4-fold at 5-50 microM. Superoxide release induced by phorbol myristate acetate or serum-activated zymosan was unaffected by either SC-45662 or SC-41661A. The regulation of superoxide generation by these compounds, both of which have the identical oxidation-reduction pharmacophore, was clearly independent of their effects on 5-LO activity. Furthermore, the mechanism by which SC-45662 and SC-41661A alter superoxide generation did not appear to depend on inhibition of xanthine oxidase, catalase or superoxide dismutase. These new compounds provide effective tools for further investigation of the relationship of these two biochemical oxidative systems.

01 Jan 1994·Advances in prostaglandin, thromboxane, and leukotriene research

Leukotrienes as mediators of nasal inflammation.

Review

Author: Murray, J J ; Knapp, H R

The three sets of studies that we have described support the notion that leukotrienes play a role in the nasal inflammatory response to allergen challenge. Strong inhibition of both leukotrienes and symptoms by A-64077, a trend toward inhibition of both leukotrienes and symptoms by SC-45662, and a lack of effect on either leukotrienes or symptoms by dietary eicosapentaenoic acid provide a consistent association between alterations of leukotrienes and nasal symptoms. A great deal of evidence has now accumulated that leukotrienes are important mediators of inflammation in vivo, but we also know that the chronic stimulus of hay fever produces a much more complex picture than seen in an acute challenge model and that many other mediators such as kinins, other peptides, histamine, and eicosanoids produced outside the 5-lipoxygenase pathway are involved (34,35). Further clinical research will be needed to develop optimal dosing regimens and delivery systems to achieve high concentrations of potent and safe 5-lipoxygenase inhibitors at sites that are critical for producing clinically useful results by modulation of the 5-lipoxygenase pathway.

100 Deals associated with SC-45662

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	-	Pfizer Inc.	-
Asthma	Phase 2	US	Pharmacia Corp.	-
Rheumatic Diseases	Phase 2	-	Pfizer Inc.	-
Rheumatic Diseases	Phase 2	US	Pharmacia Corp.	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

SC-45662

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation