Stephan James Cripps

N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275

N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.

The development and SAR of pyrrolidine carboxamide 11β-HSD1 inhibitors

The design and development of a series of highly selective pyrrolidine carboxamide 11beta-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11beta-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11beta-HSD1 selective inhibitor 42.

Synthesis of Aryl Ethers via a Sulfonyl Transfer Reaction

A general synthesis of aryl ethers from primary and secondary alcohols and aryl mesylates is presented. The reaction proceeds via a sulfonyl-transfer mechanism. In this paper, we compare the sulfonyl transfer reaction to Mitsunobu ether formation. The reaction can be employed in a multistep synthesis where the aryl mesylate is used as a phenol protecting group and then as an activating group for ether formation. This protecting/activating group strategy is demonstrated using raloxifene as the target.

N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: Strategies to eliminate reactive metabolites

N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11β-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay.

Arg-Gly thiomethylene dipeptide surrogates: Synthesis and incorporation into Arg-Gly-Asp pseudotripeptides

Abstract A synthesis of Arg-Gly thiomethylene dipeptide surrogates and the incorporation of these surrogates into Arg-Gly-Asp type pseudotripeptides are described. These compounds are potentially useful for the preparation of small nonpeptide Arg-Gly-Asp peptidomimetics and may find general utility in the fields of peptide chemistry and protein engineering.

A β-turn mimic and a thiomethylene dipeptide surrogate employed in the study of cyclic peptide RGD and RCD cell-adhesion inhibitors

During an inflammatory response, leukocytes adhere to the blood-vessel wall and to underlying extracellular matrix-protein fibronectin via noncovalent interaction through two distinct cell-surface integrins, α5β1 and α4β1. An Arg-Gly-Asp tripeptide in the cell-binding domain of fibronectin has been demonstrated to be the major site that mediates cell attachment. Our group has previously disclosed Arg-Gly-Asp- and Arg-Cys-Asp-containing cyclic peptide cell-adhesion inhibitors, which are potentially useful as anti-inflammatory agents, particularly in the treatment of asthma and rheumatoid arthritis. Subsequently, we have incorporated a β-turn dipeptide mimic and a suitably protected Arg-Gly thiomethylene dipeptide surrogate into our lead peptides by solid-phase synthesis. The preparation of the surrogates, and the structure-activity studies of the surrogate-containing peptides are described in this paper. Complete loss of cell-adhesion inhibition activity was observed in the case of incorporation of the conformationally constrained β-turn dipeptide into a cyclic Arg-Cys-Asp peptide inhibitor. Incorporation of an Arg-Gly thiomethylene dipeptide surrogate into cyclic Arg-Gly-Asp and Arg-Cys-Asp cyclic disulfide peptide inhibitors was tolerated, resulting in cyclic pseudopeptide cell-adhesion inhibitors lacking the Arg-Gly peptide amide bond.