Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake

Abstract

We report a new series of 8-membered benzo-fused lactams that inhibit cellular lipid uptake from HDL particles mediated by Scavenger Receptor, Class B, Type I (SR-BI). The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR), measuring the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is part of a previously reported diversity-oriented synthesis (DOS) library prepared via a build-couple-pair approach. Detailed structure-activity relationship (SAR) studies were performed with a selection of the original library, as well as additional analogs prepared via solution phase synthesis. These studies demonstrate that the orientation of the substituents on the aliphatic ring have a critical effect on activity. Additionally, a lipophilic group is required at the western end of the molecule, and a northern hydroxyl group and a southern sulfonamide substituent also proved to be optimal. Compound 2p was found to possess a superior combination of potency (avg. IC50 = 0.10 μM) and solubility (79 μM in PBS), and it was designated as probe ML312.

Chemical probes and drug leads from advances in synthetic planning and methodology

“…80,260 The benzannulated sultam 4 modulates lysosome acidification and thus serves as a probe for V-ATPase function, 75 which has been associated with loss of bone density and decreased kidney function, among other conditions. 261,262 Other compounds interact with targets implicated in Alzheimer’s disease ( 1 ), 71 holoprosencephaly ( 2 ), 72 schizophrenia ( 3 ), 74 inflammatory diseases ( 5 ), 76 lipid metabolism ( 6 ), 79 and coronary artery disease ( 8 ) 81 . The remaining compounds shown are described in more detail in the vignettes in the main text.…”

“…In particular, some hits have exhibited poor aqueous solubility, although medicinal chemistry efforts have been able to improve the properties of many of these compounds. 79,93,117,181,205 Next-generation libraries are currently being designed that de-emphasize the large, lipophilic structures that result from many of combinatorial chemistry’s most widely-used transformations. 243,252…”

Multiple Chemical Features Impact Biological Performance Diversity of a Highly Active Natural Product‐Inspired Library

“…[1][2][3][4][5][6][7] The production of these libraries allows for the analysis of structure-activity relationships of the compounds, which helps inform further development of probes with diverse activity. [8][9][10][11][12][13][14][15][16] Biological performance diversity can be defined as the ability of a compound library to target a broad variety of biological functions, while containing few molecules with redundant activity. Such libraries more efficiently use resources, due to a smaller library footprint, while potentially increasing hit rates.…”

Combinatorial Chemistry Online Volume 17, Issue 7, July 2015

“…These compounds are part of a previously reported diversity-oriented synthesis (DOS) library prepared via a build-couple-pair approach. Detailed structure-activity relationship (SAR) studies were performed with a selection of the original library, as well as additional analogues prepared via solution phase synthesis [14].…”