Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology. Issue 1 (1st January 2020)

• Record Type: Journal Article
• Authors: Sutherland, Hamish S.; Tong, Amy S.T.; Choi, Peter J.; Blaser, Adrian; Franzblau, Scott G.; Cooper, Christopher B.; Upton, Anna M.; Lotlikar, Manisha; Denny, William A.; Palmer, Brian D.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 1(2020)
• Publication Date: 2020-01-01
• Subjects: QMRYMJHDLXNBRO-UHFFFAOYSA-N -- QEWGKDGQEARTIV-UHFFFAOYSA-N -- USNCVNSQTQHAQU-UHFFFAOYSA-N -- FRPRYVGTVFFBKC-UHFFFAOYSA-N -- IIPFIPKNBNHEMK-UHFFFAOYSA-N -- POPGCNPYQNLCJV-UHFFFAOYSA-N -- SDKPYUVMRXCYRP-UHFFFAOYSA-N -- PWVLDHBCGYUKRP-UHFFFAOYSA-N -- IKLRGVKRRJLVGZ-UHFFFAOYSA-N -- KEAJHYWOWIQGHC-UHFFFAOYSA-N -- OTJHOGVUZJKCQX-UHFFFAOYSA-N -- MZBBNSYHLQLGGX-UHFFFAOYSA-N -- ORDWEUNZUCREOI-UHFFFAOYSA-N -- HCSVBNXMCYZZGD-UHFFFAOYSA-N -- DCPOTLPMRKZSLN-UHFFFAOYSA-N -- SENYVZCRVBCRPG-UHFFFAOYSA-N -- KHSUUGGYMNDMNP-UHFFFAOYSA-N -- SMTTVTDGHMNZCM-UHFFFAOYSA-N -- BZXFRGTWWQDIFJ-UHFFFAOYSA-N -- OPBCPCWQSDYNHT-UHFFFAOYSA-N -- WBEFLULHCBLLMW-UHFFFAOYSA-N -- FHRAUVGPQWCRCF-UHFFFAOYSA-N -- FUVWUPVZHLQUGE-UHFFFAOYSA-N -- FZHBQLNHMZHIRV-UHFFFAOYSA-N -- KJPZDCRDRIFTJI-UHFFFAOYSA-N -- AHIGFXVNBRSSME-UHFFFAOYSA-N -- NLLLHDSWFRPABH-UHFFFAOYSA-N -- COGANMWCWZCYRA-UHFFFAOYSA-N -- NTACYBOUTLKBLO-UHFFFAOYSA-N -- SQQVHZNFCHNWOK-UHFFFAOYSA-N -- NXHARKDBGPCXTI-UHFFFAOYSA-N -- PQNMJYZFRIFZGI-UHFFFAOYSA-N -- MCFBYRDKJBTBRH-UHFFFAOYSA-N -- UAWQGTLWZYKCAW-UHFFFAOYSA-N -- KREDZWRSCHANBX-UHFFFAOYSA-N -- CLVXIJHAJFAIAX-UHFFFAOYSA-N -- ZQAVZKLYPVQQII-UHFFFAOYSA-N -- ZTHXAYLSWHJAAQ-UHFFFAOYSA-N -- BNHDNLNGEQJFHJ-UHFFFAOYSA-N; CFU, colony-forming units -- hERG, the alpha subunit of a K+ channel that contributes to the electrical activity of the heart -- HPLC, high-peformance liquid chromatography -- LDA, lithium diisopropylamide -- LiTMP, lithium tetramethylpiperidide -- LORA, low oxygen recovery assay -- MABA, microplate alamar blue assay -- MIC90, minimum concentration for 90% inhibition -- M.tb, Mycobacterium tuberculosis -- TB, tuberculosis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115213
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Bedaquiline analogues with 3, 5-disubstituted-4-pyridyl C-units. High potency and attenuated hERG inhibition cf bedaquiline. 4–6.5 log units of bacterial clearance from lung in mouse model. Oral bioavailability generally 40–60%. Abstract: Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3, 5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3, 5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3, 5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.