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The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.

The binding of a drug to serum or plasma proteins enables the transport of drugs via the blood to sites of action throughout the body. For expediency we will use serum proteins throughout this discussion with the understanding that one can substitute the term plasma proteins in all experimental instances. Only the fraction of drug unbound from serum proteins is available to diffuse from the vascular system and accumulate in tissues thereby enabling interaction with therapeutic targets and accessibility to xenobiotic clearance pathways. Therefore, the extent of drug binding to serum proteins can have a significant impact on pharmacokinetic (PK) parameters such as clearance rates and volume of distribution. In addition, because only the unbound drug is available to interact with therapeutic targets, the extent of serum binding can have significant effects on the pharmacodynamic properties of a compound as well [1, 2] Determining the fraction of drug bound to serum proteins is a standard parameter evaluated in the process of drug discovery. Although the clinical importance of changes in serum protein binding has been questioned [3-8] the need for serum protein binding studies in the discovery and preclinical development stages is essential for the pharmacokinetic modeling of drugs [1, 3, 9]. The extent of serum protein binding is an important parameter used in many in vivo modeling calculations to estimate the volume of distribution, organ clearance, and for scale-up of pharmacokinetic and pharmacodynamic parameters from animal models to humans [3, 10, 11]. The convergence of several trends in the pharmaceutical industry including high speed chemical synthesis technologies, the increasing use of in silico ADME modeling together with early in vivo evaluations of lead compounds has increased the demand for serum protein binding determinations [12].

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