John K. Lynch, Ph.D.

Director of Research & Development

John oversees all research & development projects for Cedarburg Hauser Pharmaceuticals and our clients to ensure their successful outcomes.  John also serves as an expert in the areas of the synthesis of vitamin D analogs, asymmetric synthesis of oxygenated fatty acids, asymmetric allylation reactions, synthesis of different types of heterocycles and peptide conjugates.

Past Experience

• Medicinal chemistry research – metabolic diseases, aging and degenerative diseases, neuroscience.
• Process chemistry research – efficient synthesis of nicotinic compounds, platelet aggregating factor antagonists, HIV protease inhibitors, and adrenergic compounds.

Education

• Provided the foundation for construction of a key biaryl bond in the seminal total synthesis of the Vancomycin family of antibiotics in the Evans group.
• Studied macrocyclization approaches to the construction of biaryl-containing cyclic peptides. Closely examined a biomimetic, oxidative, biaryl macrocyclization for the asymmetric synthesis of Biphenomycin.
• Extensive knowledge and expertise in asymmetric synthesis, construction of unnatural amino acids, biaryl bond formation, biaryl ether formation, protection and deprotection strategies, conformational analysis and reaction mechanism.

• Contributed to the discovery of a novel, asymmetric cis hydroxylation. Constructed sets of chiral, allylic epoxides followed by the study of palladium-mediated opening of these epoxides in the presence of carbon dioxide.

The elevated expression of cell adhesion molecules (CAMs) on the lumenal surface of vascular endothelial cells is a critical early event in the complex inflammatory process. The adhesive interactions of these CAMs that include E-selectin, ICAM-1, and VCAM-1 with their counter-receptors on leukocytes, such as integrins of the aLß2 family, result in migration of the leukocytes to the site of inflammation and cause tissue injury. Pharmaceutical agents that could suppress the induced expression of one or more of these cell adhesion molecules would provide a novel mechanism to attenuate the inflammatory responses associated with chronic inflammatory diseases. A-205804 (1), a potent and selective inhibitor of the induced expression of E-selectin and ICAM-1 over VCAM-1, was further modified with emphasis at the C-4 and C-2 positions to identify a more potent drug candidate with a good pharmacokinetic profile and physical properties.

Replacement of the C-4 sulfur linkage in 1 with an oxygen atom eliminated one of the two major metabolites for this lead molecule. The para-position of the 4-phenoxy group of the thieno[2,3-c]pyridine lead is found to be very critical for a higher in vitro potency and selectivity of E-selectin and ICAM-1 over VCAM-1 expression. This position is presumably close to the solvent-accessible region of the target protein-inhibitor complex. An attempt to install a water-solubilizing group at the para-position of the phenoxy group to increase the aqueous solubility of this lead series through various linkages failed to provide an ideal inhibitor. Only small substituents such as fluorine are tolerated at the meta- and ortho-positions of the 4-phenoxy to retain a good in vitro potency. Bromo, trifluoromethyl, pyrazol-1-yl, and imidazol-1-yl are among the better substituents at the para-position. With fine-tuning at the C-2 position we discovered a series of very potent (IC50 < 5 nM for ICAM-1) and selective (>200-fold vs VCAM-1) inhibitors with a good pharmacokinetic profile. Demonstrated efficacy in a rat rheumatoid arthritis model and in a mice asthma model with selected compounds is also reported.