# Structure-based strategy for developing inhibitors of the kidney chloride channel CLC-Ka

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $617,535

## Abstract

CLCs (the “Chloride Channel” family) are anion-selective transporters and channels ubiquitous in
all organisms. Among them, CLC-Ka and CLC-Kb are essential for Cl– and water handling in the
kidney. CLC-Ka is localized to the thin ascending limb, where it helps to establish the steep solute
gradient in the inner medullary interstitium that drives renal water reabsorption. As such, CLC-Ka
is a potential drug target for treating pathologic water retention (hyponatremia) that frequently
complicates the management of patients with hypertension, heart failure, or cirrhosis. A specific
CLC-Ka inhibitor would be invaluable for validating CLC-Ka as a drug target for manipulating renal
water excretion. In this project, we leverage recent breakthroughs to develop selective CLC-Ka
inhibitors. The first breakthrough is our discovery of BIM1, a substituted benzimidazole that
displays >20-fold selectivity for CLC-Ka over its closest homolog CLC-Kb. The synthetic
accessibility of BIM derivatives makes them well suited for further development. The second
breakthrough is the revolution in cryo-electron microscopy, which enables high-resolution
structure determination of challenging targets, including ion channels. A molecular structure of
the BIM/CLC-K complex will identify which regions of the BIM molecule must be retained for
potency/selectivity and which may be modified to improve pharmacokinetic properties. Guided by
this information, we will use a medicinal chemistry approach to develop BIM derivatives with
optimized potency, selectivity, and pharmacokinetic properties. Optimized BIM derivatives will be
tested for in vivo efficacy.

## Key facts

- **NIH application ID:** 10878959
- **Project number:** 5R01DK128881-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Merritt C Maduke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $617,535
- **Award type:** 5
- **Project period:** 2021-09-20 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878959

## Citation

> US National Institutes of Health, RePORTER application 10878959, Structure-based strategy for developing inhibitors of the kidney chloride channel CLC-Ka (5R01DK128881-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10878959. Licensed CC0.

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