ABSTRACT
Avoiding cardiac liability associated with blockade of hERG (human ether a go-go) is key for successful drug discovery and development. This paper describes the work undertaken in the discovery of a potent CCR5 antagonist, maraviroc 34, for the treatment of HIV. In particular the use of a pharmacophore model of the hERG channel and a high throughput binding assay for the hERG channel are described that were critical to elucidate SAR to overcome hERG liabilities. The key SAR involves the introduction of polar substituents into regions of the molecule where it is postulated to undergo hydrophobic interactions with the ion channel. Within the CCR5 project there appeared to be no strong correlation between hERG affinity and physiochemical parameters such as pKa or lipophilicity. It is believed that chemists could apply these same strategies early in drug discovery to remove hERG interactions associated with lead compounds while retaining potency at the primary target.
Subject(s)
Anti-HIV Agents/chemistry , CCR5 Receptor Antagonists , Cyclohexanes/chemistry , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Triazoles/chemistry , Anti-HIV Agents/therapeutic use , Cyclohexanes/therapeutic use , Drug Evaluation, Preclinical , Humans , Maraviroc , Receptors, CCR5/metabolism , Triazoles/therapeutic useABSTRACT
Relationships between physicochemical drug properties and toxicity were inferred from a data set consisting of animal in vivo toleration (IVT) studies on 245 preclinical Pfizer compounds; an increased likelihood of toxic events was found for less polar, more lipophilic compounds. This trend held across a wide range of types of toxicity and across a broad swath of chemical space.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Pharmaceutical Preparations/chemistry , Structure-Activity Relationship , Animals , Dogs , Drug Evaluation, Preclinical , Female , Humans , Male , RatsABSTRACT
The design and profile of a series of indole containing long acting beta(2)-adrenoceptor agonists is described. Evaluation of these analogues using an in vitro guinea pig trachea tissue model demonstrates that analogues within this series have salmeterol-like duration of action with potential for long duration of action in humans.