Kenneth John Butcher

Application of Barluenga Boronic Coupling (BBC) to the Parallel Synthesis of Drug‐like and Drug Fragment‐like Molecules

Library and array synthesis has proven an invaluable tool for medicinal chemists to quickly assess key structure–activity relationships against a biological target. The main requirements for the adoption of a given synthetic protocol are: 1) the availability of a diverse set of monomers (building blocks), 2) the reaction should be adapted to the preparation of drug-like molecules and thus should tolerate a wide range of functional groups, and 3) the process should ideally be airand moisturetolerant. As a consequence, the protocols used for library synthesis have traditionally been biased toward polar bond formation, such as amide couplings. However, emerging C C bond formation methodologies are often crucial to establish new synthetic methods and disconnections, but publications in this field often focus on simplified substrates, yielding products of high lipophilicity (i.e. , high cLog P) and few functionalities such as hydrogen bond donors or acceptors (i.e. , low topological polar surface area (TPSA)). High cLog P and low TPSA values are correlated with a range of preclinical issues such as low solubility, promiscuity, and toxicity, and have emerged as a key descriptors of drug-likeness 3] and drug fragment-likeness. For these reasons, medicinal chemists often find recently published C C bond formation reactions ill-suited to generate new compounds with good drug-like (“rule-of-five”) and drug fragment-like (“rule-ofthree”) properties. In a recent review, MacDonald et al. elegantly demonstrate that there is limited overlap between the “synthetic space” described in recent synthetic communications and the “drug-like space” defined by the “rule-of-five” and related approaches. To assess the diversity of reactions used in parallel chemistry at our Pfizer research facility in Sandwich, we analyzed the protocols used for the preparation of more than 1300 libraries over the last 18 months (2010–2011). The protocols were pooled by bond-type formation (Figure 1). N-Acylation reactions (in which we included amide, sulfonamide, urea, and carbamate formation) accounted for a significant number (30 %) of protocols. C N bond formation (including N-alkylation, N-arylation, and reductive aminations) represented 18 % of protocols. Heterocycle formation accounted for 9 % of protocols, while C C bond formation (which includes Suzuki and Stille couplings) was only used in 8 % of protocols. The category “other” (31 %) captures both seldom-used reactions and multistep reactions: for example, a combination of the above protocols with protection/deprotection steps. These results are roughly comparable to data gathered from the medicinal chemistry literature, which show that C C bond formation reactions account for ~11 % of the methods used to prepare drug candidates. Interestingly, the overall success rates of C C bond formation protocols (67 % success rate) used in our parallel synthesis were similar to N-acylation (73 % success rate) and C N (66 % success rate) bond formation protocols. Assuming all protocols yield compounds with similar drug-like properties, these results demonstrate that although robust C C bond formation protocols are now available, this type of reaction is still underused by medicinal chemists for the preparation of library compounds. In this context, the Barluenga boronic coupling (BBC) recently caught our attention. This novel reaction involves the formation of a C C bond between a diazo compound (generated in situ from a para-toluenesulfonyl (tosyl) hydrazone) and a boronic acid through a reductive coupling (Scheme 1). Of special interest to us was the fact that a small number of examples (four out of 27) included polar functional groups such as anilinic NH2 and N H heterocycles, and the synthesis of a single small, highly polar drug-like molecule (compound 1) was indeed exemplified. The average isolated yields are consistently high (>80 %) with only two examples <60 % (two of 27). Given the ease of preparation of tosylhydrazones from a Figure 1. Distribution of synthetic protocols used for the synthesis of over 1300 libraries included in this survey, representing ~90 000 compounds successfully prepared; overall success rate: 60 %.

Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7

A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.