We compare three antagonists with equal potency in vitro against activation of a GPCR and find that two compounds which are orally bioavailable and strictly obey the drug-likeness guidelines have inferior efficacy, even oral efficacy, to a third compound that comprehensively violates these rules and has dramatically reduced oral bioavailability. We focus on a G protein-coupled receptor (GPCR) as the target, this class accounting for around one third of all small molecule pharmaceuticals in the marketplace. Here we debunk the almost universal perception that drugs need to be developed by increasing receptor affinity, potency, drug-likeness (rule-of-five compliance) and oral bioavailability. On the other hand they have become so popular that researchers and companies usually now dismiss out of hand those compounds that violate these rules as being poor choices as drug leads for further development. On the one hand these ‘rules’ have been extremely valuable and led to many translational successes in the clinic. For example, compounds with low molecular weight (MW <500), few hydrogen bond donors (HBD ≤5) and acceptors (HBA ≤10), moderate calculated octanol-water partition coefficients (ClogP 1–5), few rotatable bonds (n <12) and low polar surface area (tPSA < 140 Å 2) are thought to give the best chances of producing orally bioavailable compounds suitable for clinical development 1, 2, 3. Over the past two decades, the search for new pharmaceuticals has been heavily constrained by the imposition of rigorous rules, originally proposed only as guidelines based on empirical experimental observations 1, 2, 3, for developing orally bioavailable drugs. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents.ĭrug discovery, development and translation have relied heavily upon optimizing ligand affinity for a specific receptor, enhancing functional potency and selectivity, and improving drug-like properties for optimal pharmacokinetics and oral bioavailability. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. ![]() Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action ( t 1/2 ~ 20 h) than W54011 or JJ47 ( t 1/2 ~ 1–3 h) in inhibiting macrophage responses. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability.
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