The observed PNP and NP fragment density increases may have mostly occurred intuitively, rather than by 'NP design', because the most frequently used NP fragments (Figure ) are all very wellknown to, and commonly employed by, medicinal chemists. One example of the application of an NP moiety in lead optimisation is the use of R-(+)-carvone in the discovery of the JAK kinase inhibitor tofacitinib, 51 itself a PNP.