David A. Whipple

Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant Rejection

There is a critical need for safer and more convenient treatments for organ transplant rejection and autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved in the signaling of multiple cytokines important for various T cell functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimidine-based series of inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast proliferation assay. Select compounds were evaluated in rodent efficacy models of allograft rejection and destructive inflammatory arthritis. Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for treatment of autoimmune diseases and organ transplant rejection.

Relationship between structure and bioavailability in a series of hydroxamate based metalloprotease inhibitors

Pharmacokinetic parameters for a series of C-terminally modified hydroxamate dipeptides were evaluated by in vitro and in vivo models. The presence of a tertiary base at the C-terminus significantly reduced biliary excretion and increased plasma half-life. Moreover, introduction of a thioether functionality produced a more favorable pharmacokinetic profile compared to the corresponding oxo- and aza-analogs.

Discovery of azetidinyl ketolides for the treatment of susceptible and multidrug resistant community-acquired respiratory tract infections.

Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.

Preparation, Gram-Negative Antibacterial Activity, and Hydrolytic Stability of Novel Siderophore-Conjugated Monocarbam Diols

A novel series of monocarbam compounds exhibiting promising antibacterial activity against multidrug resistant Gram-negative microorganisms is reported, along with the synthesis of one such molecule MC-1 (1). Also reported are structure-activity relationships associated with the in vitro and in vivo efficacy of 1 and related analogues in addition to the hydrolytic stability of such compounds and possible implications thereof.

Cyclic homopentapeptides 3. Synthetic modifications to the capreomycins and tuberactinomycins: Compounds with activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci

Abstract Modification and replacement of the β-lysine side chain of capreomycin and tuberactinomycin cyclic pentapeptide derivatives resulted in compounds with good antibacterial potency against multidrug-resistant pathogens.

Cyclic homopentapeptides. 1. Analogs of tuberactinomycins and capreomycin with activity against vancomycin-resistant enterococci and Pasteurella

Abstract A 6a-(3′,4′-dichlorophenylamino) analog of viomycin was uncovered by a high-throughput screen against the animal health pathogen Pasteurella haemolytica, and has served as a novel lead structure for our infectious disease programs. We report herein the synthesis and activity of analogs of tuberactinomycins and capreomycin that are active against Pasteurella spp., methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci. This paper describes the synthesis and activity of some C-6a-substituted analogs of tuberactinomycins and capreomycin, which are active against Pasteurella spp., methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci.