Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acetamides

Journal of Medicinal Chemistry
R D DillardJ P Wery

Abstract

Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure--activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.

References

Jan 1, 1979·Journal of Medicinal Chemistry·M E FlaughB D Sawyer
Aug 30, 1989·Biochemical and Biophysical Research Communications·A KandaM Okamoto
Jul 1, 1989·Journal of Biochemistry·J J SeilhamerL K Johnson
Feb 1, 1994·Annals of Surgery·A A SantosC A Dinarello

❮ Previous
Next ❯

Citations

Mar 30, 2011·Analytical and Bioanalytical Chemistry·Kei YamamotoMakoto Murakami
Jun 24, 2010·Journal of Molecular Modeling·Preethi BadrinarayanG Narahari Sastry
Jan 15, 2013·Journal of Molecular Modeling·Kalarickal Vijayan DileepChittalakkottu Sadasivan
Mar 7, 2001·European Journal of Medicinal Chemistry·M PintoreJ R Chrétien
Jul 9, 2008·Journal of Medicinal Chemistry·Rob C OslundMichael H Gelb
Apr 15, 2008·Annual Review of Biochemistry·Gérard Lambeau, Michael H Gelb
Sep 3, 2010·Expert Opinion on Investigational Drugs·Robert S RosensonColin Hislop
Dec 26, 2018·Chemical Biology & Drug Design·Shengde ZhangAixia Yan
Apr 10, 2003·Journal of Enzyme Inhibition and Medicinal Chemistry·Fabrice PagniezPatrice Le Pape
Mar 13, 2014·Chemical Biology & Drug Design·Shunchen QiuLuhua Lai
Oct 2, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ryung Rae KimW Bret Church
Aug 17, 2002·Bioorganic & Medicinal Chemistry Letters·Sharon RossiterPeter Wardman
Jun 9, 2009·Journal of Chemical Information and Modeling·Bo LiLihe Zhang
Mar 22, 2018·Journal of Agricultural and Food Chemistry·Mohamed A FaragLudger A Wessjohann
Mar 13, 2019·Organic Letters·Carol M TaylorBenson J Edagwa

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.