Discovery and Structure Activity Relationship Optimization of a Novel Rv1625c Agonist Chemotype with Antitubercular Activity
- 1Calibr-Skaggs Institute for Innovative Medicines, a division of Scripps Research
Abstract
Rv1625c/Cya has emerged as a promising target for the development of treatment-shortening therapies for tuberculosis. Screening of an Enamine compound library identified sBQQ004 as an initial hit, and rapid hit optimization led to compound 1, which was subsequently confirmed as an Rv1625c/Cya agonist. Structure activity relationship studies identified lead compound 25 with potent activity against Mycobacterium tuberculosis H37Rv under cholesterol-dependent growth conditions (MIC = 0.27 uM) and strong intramacrophage activity (EC50 = 0.079 uM). Compounds 1 and 25 showed oral bioavailabilities of 84.5% and 51.9% in mice, respectively. Repeat BID dosing of compound 1 resulted in a dose- and time-dependent decrease in systemic exposure. Despite this pharmacokinetic limitation, the potency and overall profile of this chemotype encouraged continued optimization.
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BibTeX
@misc{xie2026discovery,
title = {{Discovery and Structure Activity Relationship Optimization of a Novel Rv1625c Agonist Chemotype with Antitubercular Activity}},
author = {H. Xie and P. Sukheja and K. Tolentino and J. Webb and A. Woods and V. Chi and D. Kathayat and C. R. Montague and B. C. VanderVen and L. Winneroski and G. Durst and D. Mendel and P. Hipskind and K. Henry and C. W. McNamara and B. Yang and A. K. Chatterjee},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752203},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752203v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Discovery and Structure Activity Relationship Optimization of a Novel Rv1625c Agonist Chemotype with Antitubercular Activity
AU - H. Xie
AU - P. Sukheja
AU - K. Tolentino
AU - J. Webb
AU - A. Woods
AU - V. Chi
AU - D. Kathayat
AU - C. R. Montague
AU - B. C. VanderVen
AU - L. Winneroski
AU - G. Durst
AU - D. Mendel
AU - P. Hipskind
AU - K. Henry
AU - C. W. McNamara
AU - B. Yang
AU - A. K. Chatterjee
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752203
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752203v1
AB - Rv1625c/Cya has emerged as a promising target for the development of treatment-shortening therapies for tuberculosis. Screening of an Enamine compound library identified sBQQ004 as an initial hit, and rapid hit optimization led to compound 1, which was subsequently confirmed as an Rv1625c/Cya agonist. Structure activity relationship studies identified lead compound 25 with potent activity against Mycobacterium tuberculosis H37Rv under cholesterol-dependent growth conditions (MIC = 0.27 uM) and strong intramacrophage activity (EC50 = 0.079 uM). Compounds 1 and 25 showed oral bioavailabilities of 84.5% and 51.9% in mice, respectively. Repeat BID dosing of compound 1 resulted in a dose- and time-dependent decrease in systemic exposure. Despite this pharmacokinetic limitation, the potency and overall profile of this chemotype encouraged continued optimization.
ER -