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.

Aryl sulfonamido indane inhibitors of the Kv1.5 ion channel.

A collection of aryl sulfonamido indanes based on the lead compound 1 was synthesized and evaluated for Kv1.5 inhibitory activity. Kv1.5 inhibitors have the potential to be atrium-selective agents for treatment of atrial fibrillation. (1R,2R)-1 has an IC(50) of 0.033microM against Kv1.5 and is selective against other cardiac ion channels, including hERG.

Preparation of unsymmetrical sulfonylureas from N,N'-sulfuryldiimidazoles.

The synthetic methods reported in the literature for the preparation of sulfonylureas tend to be restricted in scope or unsuitable for use in parallel synthesis. We have developed a method for preparing sterically congested sulfonylureas based on N,N'-sulfuryldiimidazole that is both convenient and amenable to parallel synthesis. Sequential activation by way of alkylation of the imidazole group using methyl triflate followed by nucleophilic displacement with a variety of amines and anilines afford the unsymmetrical sulfonylurea. Sulfonylureas prepared from anilines were obtained in high yields using N,N'-sulfuryldiimidazole, while the somewhat more sterically congested analogue, N,N'-sulfurylbis-2-methylimidazole, proved to be superior for alkylamines.

Stereoselective Synthesis of Differentially Protected Derivatives of the Higher Amino Sugars Destomic Acid and Lincosamine from Serine and Threonine.

The aminoheptose destomic acid (3.5) and the aminooctose lincosamine (6.8) were synthesized in protected form by parallel sequences starting from the oxazolidine derivatives 2.4 and 5.1 of N-CBz serinal and N-BOC threoninal. The parallel sequences feature BF(3)-promoted addition of the (R)-gamma-OTBS allylic stannane 2.8 to the homologated enals 2.7 and 5.4, respectively, followed by stereoselective bis-dihydroxylation of the derived bis-OTBS ethers 2.10 and 5.6. Regioselective oxidative cleavage of the less hindered vicinal diol moieties of these intermediates led to the gamma-lactols 3.2 and 5.8, respectively. In the former case, treatment with TBAF and subsequent hydrolysis removed the OTBS and acetonide protecting groups affording the destomic acid precursor, pyranose 3.4. Lactol 5.8 was converted to the pyranoside 6.3 by silyl ether cleavage, acidic hydrolysis, and bis-acetonide formation. Inversion of the C7 hydroxyl grouping was effected by the Mitsunobu methodology with p-NO(2)C(6)H(4)CO(2)H. Subsequent hydrolysis, cleavage of the BOC grouping, and N-acetylation afforded the lincosamine derivative 6.7.