Joseph J. Mcdonald

Assessment of docking poses: Interactions-based accuracy classification (IBAC) versus crystal structure deviations

Six docking programs (FlexX, GOLD, ICM, LigandFit, the Northwestern University version of DOCK, and QXP) were evaluated in terms of their ability to reproduce experimentally observed binding modes (poses) of small-molecule ligands to macromolecular targets. The accuracy of a pose was assessed in two ways: First, the RMS deviation of the predicted pose from the crystal structure was calculated. Second, the predicted pose was compared to the experimentally observed one regarding the presence of key interactions with the protein. The latter assessment is referred to as interactions-based accuracy classification (IBAC). In a number of cases significant discrepancies were found between IBAC and RMSD-based classifications. Despite being more subjective, the IBAC proved to be a more meaningful measure of docking accuracy in all these cases.

Orally Active MMP-1 Sparing α-Tetrahydropyranyl and α-Piperidinyl Sulfone Matrix Metalloproteinase (MMP) Inhibitors with Efficacy in Cancer, Arthritis, and Cardiovascular Disease

α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMPs-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.

Synthesis and activity of selective MMP inhibitors with an aryl backbone

A series of novel, MMP-1 sparing arylhydroxamate sulfonamides with activity against MMP-2 and -13 is described.

Design of potent inhibitors of human beta-secretase. Part 2.

We describe an optimized series of acyclic hydroxyethylamine transition state isosteres of beta-secretase that incorporates a variety of P(2) side chains that yield potent inhibitors with excellent cellular activity. A 2.2A crystal structure of compound 13 is shown.

Discovery of Potent Inhibitors of Soluble Epoxide Hydrolase by Combinatorial Library Design and Structure-Based Virtual Screening

Structure-based virtual screening was applied to design combinatorial libraries to discover novel and potent soluble epoxide hydrolase (sEH) inhibitors. X-ray crystal structures revealed unique interactions for a benzoxazole template in addition to the conserved hydrogen bonds with the catalytic machinery of sEH. By exploitation of the favorable binding elements, two iterations of library design based on amide coupling were employed, guided principally by the docking results of the enumerated virtual products. Biological screening of the libraries demonstrated as high as 90% hit rate, of which over two dozen compounds were single digit nanomolar sEH inhibitors by IC(50) determination. In total the library design and synthesis produced more than 300 submicromolar sEH inhibitors. In cellular systems consistent activities were demonstrated with biochemical measurements. The SAR understanding of the benzoxazole template provides valuable insights into discovery of novel sEH inhibitors as therapeutic agents.

Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain.

Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate.

Orally Bioavailable Dual MMP-1/MMP-14 Sparing, MMP-13 Selective Alpha-sulfone Hydroxamates

A series of phenyl piperidine alpha-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13, are dual-sparing of MMP-1 and MMP-14 (MT1-MMP) and exhibit oral bioavailability in rats.

Selective, orally active MMP inhibitors with an aryl backbone

This letter describes SAR exploration and rat PK optimization of a series of novel, MMP-1 sparing aryl hydroxamate sulfonamides with activity against MMP-2 and MMP-13.

Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 1: Identification of 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane as lead scaffolds

Herein we report the identification of two new fatty acid amide hydrolase (FAAH) inhibitor lead series with FAAH k(inact)/K(i) potency values greater than 1500M(-1)s(-1). The two novel spirocyclic cores, 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane, clearly distinguished themselves from the other spirocyclic cores on the basis of their superior potency for FAAH. Lead compounds from these two series have suitable FAAH potency and selectivity for additional medicinal chemistry optimization.

Identification of Type-II Inhibitors Using Kinase Structures.

Spleen tyrosine kinase is a non‐receptor tyrosine kinase, overactivation of which is thought to contribute to autoimmune diseases as well as allergy and asthma. Protein kinases have a highly conserved ATP binding site, thus making challenging the design of selective small molecule inhibitors. It has been well documented that some protein kinases can be stabilized in their inactive conformations (Type‐II inhibitors). Herein, we describe a protein structure/ligand‐based approach to successfully identify ligands that bind to novel conformations of spleen tyrosine kinase. By utilizing kinase protein crystal structures both in the public domain (RCSB) and within Pfizer’s protein crystal database, we report the discovery of the first spleen tyrosine kinase Type‐II ligands. Compounds 1 and 3 were found to bind to the DFG‐out conformation of spleen tyrosine kinase, while compound 2 binds to a DFG‐in, C‐Helix‐out conformation. In this instance, the C‐helix moved significantly to create a large hydrophobic pocket rarely seen in kinase protein crystal structures.