Biarylcarboxylic Acids and -amides:  Inhibition of Phosphodiesterase Type IV versus [³H]Rolipram Binding Activity and Their Relationship to Emetic Behavior in the Ferret

Abstract

In addition to having desirable inhibitory effects on inflammation, anaphylaxis, and smooth muscle contraction, PDE-IV inhibitors also produce undesirable side effects including nausea and vomiting. In general, compounds that inhibit PDE-IV also potently displace [3H]rolipram from a high-affinity binding site in rat cortex. While this binding site has not been identified, it has been proposed to be an allosteric binding site on the PDE-IV enzyme. Preliminary studies have suggested that the emetic potency of PDE-IV inhibitors is correlated with affinity for the brain rolipram binding site rather than potency at inhibiting PDE-IV enzyme activity. Efforts to eliminate the emetic potential of PDE-IV inhibitors were directed toward developing compounds with decreased [3H]rolipram binding affinity while retaining PDE-IV potency. Thus, a novel series of 4-(3-alkoxy-4-methoxyphenyl)benzoic acids and their corresponding carboxamides were prepared and evaluated for their PDE-IV inhibitory and rolipram binding site properties. Modification of the catechol ether moiety led to phenylbutoxy and phenylpentoxy analogues that provided the desired activity profile. Specifically, 4-[3-(5-phenylpentoxy)-4-methoxyphenyl]-2-methylbenzoic acid, 18, was found to exhibit potent PDE-IV inhibitory activity (IC50 0.41 microM) and possessed 400 times weaker activity than rolipram for the [3H]rolipram binding site. In vivo, compound 18 was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 8.8 mg/kg, po) and demonstrated a significant reduction in emetic side effects (ferret, 20% emesis at 30 mg/kg, po).

Inhibitor Binding to Type 4 Phosphodiesterase (PDE4) Assessed Using [3H]Piclamilast and [3H]Rolipram

“…However, central nervous system and gastrointestinal side effects remain a problem, limiting clinical development. It has been speculated that some of the side effects may be mediated through inhibitor interaction with the high-affinity rolipram binding site (HARBS) on PDE4 (Barnette et al, 1995;Duplantier et al, 1996); rolipram and a number of other PDE4 inhibitors have been shown to bind with low nanomolar affinity to this site (Schneider et al, 1986;Torphy et al, 1992;Jacobitz et al, 1996).…”

CHF6001 II: A Novel Phosphodiesterase 4 Inhibitor, Suitable for Topical Pulmonary Administration—In Vivo Preclinical Pharmacology Profile Defines a Potent Anti-Inflammatory Compound with a Wide Therapeutic Window

“…Because emesis is at least in part a side effect mediated by the central nervous system, new PDE4 inhibitors with low brain penetration have been developed, but this approach has not yielded better tolerated compounds, given that the area postrema, which acts as chemoreceptor trigger zone for emesis, is not protected by the blood-brain barrier and that PDE4 inhibitors also exert direct effects on the gastrointestinal tract (Okuda et al, 2009). Alternative strategies were to selectively target the low-affinity rolipram-binding site conformer of PDE4 over the high-affinity rolipram-binding conformer (Barnette et al, 1996;Rocque et al, 1997) or the isoform PDE4B over the isoform PDE4D (Robichaud et al, 2002b;Lehnart et al, 2005), but both these approaches have been only partially validated (Duplantier et al, 1996).…”

Peripheral Phosphodiesterase 4 Inhibition Produced by 4-[2-(3,4-Bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826,141) Prevents Experimental Autoimmune Encephalomyelitis

“…Accumulating evidence suggesting that PDE4 inhibitors reduce EAE severity has led to the proposal that such compounds may have therapeutic potential for treating MS (Burnouf and Pruniaux, 2002). Unfortunately, a complication with many PDE4 inhibitors is their ability to readily cross the blood-brain barrier, accumulate in the CNS, and trigger nausea and emesis (Duplantier et al, 1996;Burnouf and Pruniaux, 2002). In this study, we have shown that a novel nonbrain penetrant PDE4 inhibitor, L-826,141, significantly delays the onset and severity of EAE administered either before or after the initial onset of clinical symptoms.…”

“…Nausea and emesis remain a large concern in the development of PDE4 inhibitors (Duplantier et al, 1996). Although rodents do not vomit, it is still possible to distinguish whether the mice are experiencing discomfort as a direct result of constant central PDE4 inhibition.…”