The Pharmacology of DMP696 and DMP904, Non‐Peptidergic CRF1 Receptor Antagonists

Yu‐Wen Li; Lawrence Fitzgerald; Harvey Wong; Snjezana Lelas; Ge Zhang; Mark D Lindner; Tanya Wallace; John McElroy; Nicholas J Lodge; Paul Gilligan; Robert Zaczek

doi:10.1111/j.1527-3458.2005.tb00034.x

. 2006 Jun 7;11(1):21–52. doi: 10.1111/j.1527-3458.2005.tb00034.x

The Pharmacology of DMP696 and DMP904, Non‐Peptidergic CRF₁ Receptor Antagonists

Yu‐Wen Li ^1,^✉, Lawrence Fitzgerald ^1,^*, Harvey Wong ¹, Snjezana Lelas ¹, Ge Zhang ¹, Mark D Lindner ¹, Tanya Wallace ¹, John McElroy ¹, Nicholas J Lodge ¹, Paul Gilligan ¹, Robert Zaczek ¹

PMCID: PMC6741745 PMID: 15867951

ABSTRACT

CRF₁ antagonists DMP696 and DMP904 were designed as drug development candidates for the treatment of anxiety and depression. Both compounds display nanomolar affinity for human CRF₁ receptors, and exhibit >1000‐fold selectivity for CRF₁ over CRF₂ receptors and over a broad panel of other proteins. DMP696 and DMP904 block CRF‐stimulated adenylyl cyclase activity in cortical homogenates and cell‐lines expressing CRF₁ receptors. Both compounds inhibit CRF‐stimulated ACTH release from rat pituitary corticotropes. Binding and functional studies indicate that DMP696 and DMP904 behave as noncompetitive full antagonists. DMP696 and DMP904 exhibit anxiolytic‐like efficacy in several rat anxiety models. In the defensive withdrawal test, both compounds reduce exit latency with lowest effective doses of 3 and 1 mg/kg, respectively. The anxiolytic‐like effect is maintained over 14 days of repeated dosing. In the context of a novel environment used in this test, DMP696 and DMP904 reverse mild stress‐induced increases in plasma CORT secretion but at doses 3‐4‐fold greater than those required for anxiolytic‐like efficacy. DMP696 and DMP904 are ineffective in three depression models including the learned helplessness paradigm at doses up to 30 mg/kg. At lowest anxiolytic‐like doses, DMP696 and DMP904 occupy >50% CRF₁ receptors in the brain. The in vivo IC₅₀ values (plasma concentrations required for occupying 50% CRF₁ receptors) estimated based upon free, but not total, plasma concentrations are an excellent correlation with the in vitro IC₅₀ values. Neither compound produces sedation, ataxia, chlordiazepoxide‐like subjective effects or adverse effects on cognition at doses 10‐fold higher than anxiolytic‐like doses. Neither compound produces physiologically significant changes in cardiovascular, respiratory, gastrointestinal or renal functions at anxiolytic‐like doses. DMP696 and DMP904 have favorable pharmacokinetic profiles with good oral bioavailabilities. The overall pharmacological properties suggest that both compounds may be effective anxiolytics with low behavioral side effect liabilities.

Keywords: Anxiety, Corticotropin‐releasing factor (CRF), CRF Antagonists, Depression, DMP696, DMP904

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The Pharmacology of DMP696 and DMP904, Non‐Peptidergic CRF₁ Receptor Antagonists

Yu‐Wen Li

Lawrence Fitzgerald

Harvey Wong

Snjezana Lelas

Ge Zhang

Mark D Lindner

Tanya Wallace

John McElroy

Nicholas J Lodge

Paul Gilligan

Robert Zaczek

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The Pharmacology of DMP696 and DMP904, Non‐Peptidergic CRF1 Receptor Antagonists

Yu‐Wen Li

Lawrence Fitzgerald

Harvey Wong

Snjezana Lelas

Ge Zhang

Mark D Lindner

Tanya Wallace

John McElroy

Nicholas J Lodge

Paul Gilligan

Robert Zaczek

ABSTRACT

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The Pharmacology of DMP696 and DMP904, Non‐Peptidergic CRF₁ Receptor Antagonists