Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation

Shawn P. Walsh; Aurash Shahripour; Haifeng Tang; Nardos Teumelsan; Jessica L. Frie; Yuping Zhu; Birgit T. Priest; Andrew M. Swensen; Jessica Liu; Michael Margulis; Richard Visconti; Adam B. Weinglass; John P. Felix; Richard M. Brochu; Timothy Bailey; Brande Thomas-Fowlkes; Magdalena Alonso‐Galicia; Xiaoyan Zhou; Lee-Yuh Pai; Aaron Corona; Caryn Hampton; Melba Hernandez; Ross Bentley; Jing Chen; Kashmira Shah; Joseph M. Metzger; Michael J. Forrest; Karen Owens; Vincent Tong; Sookhee Ha; Sophie Roy; Gregory J. Kaczorowski; Lihu Yang; Emma R. Parmee; María L. García; Kathleen A. Sullivan; Alexander Pasternak

doi:10.1021/ml500440u

Key Points

To identify and optimize a selective and potent ROMK inhibitor with pharmacokinetic properties appropriate for preclinical evaluation as a novel diuretic.
Optimized an initial screening hit into a new structural subseries, leading to compound 28.
Profiled selectivity against related ion channels and characterized pharmacokinetic parameters across preclinical species.
Tested in vivo pharmacodynamic activity in Sprague-Dawley rats and dogs.
Compound 28 showed high selectivity for ROMK inhibition compared to related ion channels.
Pharmacokinetic evaluations demonstrated favorable drug-like properties across multiple preclinical animal models.
In vivo testing showed robust pharmacodynamic diuretic responses in both rats and dogs.

Structured PICO

P

Population

Preclinical models including Sprague-Dawley rats, female mongrel dogs, rhesus monkeys, anesthetized guinea pigs, and HEK-293 cells.

I

Intervention

ROMK inhibitor (R,S)-28 administered orally or intravenously

C

Comparator

Vehicle control, hydrochlorothiazide (HCTZ 25 mpk), and previously reported ROMK inhibitor 6

O

Outcome

Diuresis, natriuresis, and kaliuresis, along with pharmacokinetic parameters (clearance, half-life, oral bioavailability) and in vitro ROMK/hERG inhibitionsurrogate

The novel ROMK inhibitor (R,S)-28 demonstrates robust diuresis and natriuresis without kaliuresis in preclinical models, with a pharmacokinetic profile suitable for once-daily oral dosing.

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Implication

Preclinical diuresis without kaliuresis supports ROMK inhibitor development; leaves open translation to human efficacy and safety.

Abstract

A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated.

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Cite This Study

Walsh et al. (2015) studied this question.

synapsesocial.com/papers/6a7dcac93fa445558d7d889d https://doi.org/10.1021/ml500440u

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Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation

Key Points

Structured PICO

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation

Key Points

Structured PICO

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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