Structure activity relationships of new inhibitors of mammalian 2,3-oxidosqualene cyclase designed from isoquinoline derivatives

Chemical & Pharmaceutical Bulletin
Jean BinetP P Renaut

Abstract

We have designed more potent inhibitors from the previously reported LF 05-0038, a 6-isoquinolinol based inhibitor of 2,3-oxidosqualene cyclase (IC50: 1.1 microM). Replacement of the 3-OH group by various 3-substituted amino groups, and modification of the alkyl chain borne by the endocyclic nitrogen led to inhibitors with IC50 in the range of 0.15 to 1 microM. In a second step, opening of the bicyclic ring system afforded the corresponding aminoalkylpiperidines which were slightly more potent. Finally, introduction of suitable aromatic containing moieties on the piperidine nitrogen yielded very potent inhibitors such as 20x (IC50 = 18 nM) easy to synthesize and achiral. The recent availability of the crystal structure of squalene-hopene cyclase allowed us to construct a three-dimensional (3D) model of the related 2,3-oxidosqualene cyclase (OSC) which was tentatively used to describe the possible mode of binding of our compounds and which can be useful for designing new inhibitors.

References

Mar 1, 1981·Antimicrobial Agents and Chemotherapy·A GeorgopoulosJ Drews
Sep 26, 1995·Proceedings of the National Academy of Sciences of the United States of America·I Abe, G D Prestwich
Sep 20, 1997·Science·K U WendtG E Schulz
Feb 5, 1999·Journal of Molecular Biology·K U WendtG E Schulz
Oct 12, 2000·Angewandte Chemie·K U WendtD R Liu

❮ Previous
Next ❯

Citations

Oct 13, 2011·IUBMB Life·Laura TrapaniValentina Pallottini
Jul 11, 2003·Journal of Medicinal Chemistry·Henrietta DehmlowOlivier H Morand
Apr 20, 2006·Bioorganic & Medicinal Chemistry·Ulrik HillaertSerge Van Calenbergh
May 16, 2003·Journal of Medicinal Chemistry·Alexander LenhartGeorg E Schulz

❮ 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.