Herein, we describe the discovery and optimisation of a series of potent and selective TRPV4 antagonists. The application of a variety of computational techniques (including Bayesian modelling) at the HTS triage stage enabled the early deprioritisation of likely frequent hitters. The use of methods to positively prioritise compounds for follow-up screening allowed the rapid identification of a number of interesting TRPV4 antagonist series. The hit-to-lead efforts in one such series, the hydroxypiperidines, will be described.