Identification of SQ609 as a lead compound from a library of dipiperidines

Abstract

We recently reported that compounds created around a dipiperidine scaffold demonstrated activity against Mycobacterium tuberculosis (Mtb) (Bogatcheva, E.; Hanrahan, C.; Chen, P.; Gearhart, J.; Sacksteder, K.; Einck, L.; Nacy, C.; Protopopova, M. Bioorg. Med. Chem. Lett.2010, 20, 201). To optimize the dipiperidine compound series and to select a lead compound to advance into preclinical studies, we evaluated the structure-activity relationship (SAR) of our proprietary libraries. The (piperidin-4-ylmethyl)piperidine scaffold was an essential structural element required for antibacterial activity. Based on SAR, we synthesized a focused library of 313 new dipiperidines to delineate additional structural features responsible for antitubercular activity. Thirty new active compounds with MIC 10-20μg/ml on Mtb were identified, but none was better than the original hits of this series, SQ609, SQ614, and SQ615. In Mtb-infected macrophages in vitro, SQ609 and SQ614 inhibited more than 90% of intracellular bacterial growth at 4μg/ml; SQ615 was toxic to these cells. In mice infected with Mtb, weight loss was completely prevented by SQ609, but not SQ614, and SQ609 had a prolonged therapeutic effect, extended by 10-15days, after cessation of therapy. Based on in vitro and in vivo antitubercular activity, SQ609 was identified as the best-in-class dipiperidine compound in the series.

The Biosynthesis of Capuramycin-type Antibiotics

“…Thus, the data are consistent with direct incorporation of L-Thr via a transaldollike mechanism. Additionally, a 13 C-15 N heteronuclear spin coupling at C-6Ј of the 13 C-NMR spectrum (J CN ϭ 18 Hz) was detected that, along with analysis of the LC-MS spectrum (data not shown), is consistent with concomitant 15 N incorporation from L-Thr during the biosynthesis of CarU.…”

“…Studies into the biological activity of A-500359 A, the major congener isolated from S. griseus SANK 60196, and several semisynthetic analogues have revealed a potential utility of these natural products as anti-tuberculosis antibiotics (9,10). For example, SQ641 and SQ922, two leads under preclinical development by Sequella (Rockville, MD), have been shown to have several clinically desirable attributes, including in vitro activity against multiple-drug-resistant strains of Mycobacterium tuberculosis (the primary causative agent of tuberculosis); high efficacy in a murine model of tuberculosis; rapid kill time in vitro and in vivo; and no toxicity to mice (11)(12)(13)(14)(15)(16)(17). Given the widespread documentation of extensively drug-resistant M. tuberculosis and the recent reality of totally drug-resistant M. tuberculosis (18), the development of drugs with novel targets, such as the capuramycin-type antibiotics, makes them attractive leads for tuberculosis chemotherapy (19,20).…”

Investigational Antimicrobial Agents of 2013

“…It displayed promising anti-M. tuberculosis activity, including against MDR isolates, with a mechanism that targets the mycobacterial cell wall (http://www.sequella.com). SQ609 demonstrated good activity against M. tuberculosis strains, inhibiting more than 90% of intracellular bacterial growth at 4 g/ml without toxicity (244). In addition, in vivo efficacy was demonstrated in a mouse infection model, where it completely prevented TBinduced weight loss and improved survival compared to results for mice treated with moxifloxacin or ethambutol.…”

“…SQ609 (Sequella, Inc.) (Fig. 7, compound 8), an adamantine-containing hydroxydipiperidine, was identified after screening a 10,240-compound library based on commercially available amino acids and containing a dipiperidine pharmacophore (244). It displayed promising anti-M. tuberculosis activity, including against MDR isolates, with a mechanism that targets the mycobacterial cell wall (http://www.sequella.com).…”

Discovery and Development of SQ109: A New Antitubercular Drug with a Novel Mechanism of Action

“…The most frequently occurring fragments in the active compounds were: highly α-branched aliphatic moieties, 2,2-diphenylethyl and 3,3-diphenylpropyl fragments, tricyclic skeletons derived from adamantane-containing amine monomers, myrtanylamine and isopinocamphylamine and isoprenoid structures. We used this SAR to create a new 30,000+ diamine library to further develop the structural diversity of our library by modification of the diamine linker, which led to the discovery of novel scaffolds with activity against Mtb [51–53]. …”