title: 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 10-20 μg/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 4 μg/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 10-15 days, 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.
authors.affiliation: Sequella, Inc., 9610 Medical center Drive, Suite 200, Rockville, MD 20850, USA. elenabogatcheva@sequella.com
authors.forename: Elena
authors.initials: E
authors.lastname: Bogatcheva
authors.forename: Colleen
authors.initials: C
authors.lastname: Hanrahan
authors.forename: Boris
authors.initials: B
authors.lastname: Nikonenko
authors.forename: Gladys
authors.initials: G
authors.lastname: de los Santos
authors.forename: Venkata
authors.initials: V
authors.lastname: Reddy
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Francis
authors.initials: F
authors.lastname: Barbosa
authors.forename: Leo
authors.initials: L
authors.lastname: Einck
authors.forename: Carol
authors.initials: C
authors.lastname: Nacy
authors.forename: Marina
authors.initials: M
authors.lastname: Protopopova
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008809:Mice, Inbred C3H; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000995:Antitubercular Agents; D010880:Piperidines; C568621:SQ 609; D054852:Small Molecule Libraries; D000218:Adamantane