In this work, a novel technique for molecular design is explored by generating compounds to replace R-141b in polyurethane foam blowing applications. This technique, which is known as the inverse quantitative structure-activity relationship (I-QSAR) method, is based on solving the inverse problem of molecular design, using a newly developed descriptor called Signature. In this work, we optimize the properties of the candidate solutions based on the normal boiling point and the vapor-phase thermal conductivity. After generating more than 3 million solutions with this technique, we have identified seven compounds for further study. Unlike other inverse design techniques, I-QSAR with Signature does not use a template compound and, thus, nonintuitive candidates with optimal predicted properties can result. The seven best candidates that form the focused database include straight chains and rings of a variety of sizes with one or two O atoms in the ring.