An asymmetric synthesis of (2S,5S)-5-substituted azepane-2-carboxylate derivatives.

To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large scale preparation. To this end we have successfully developed a scalable asymmetric synthesis of these derivatives that starts with known hydroxy-ketone 8. The key step features an oxidative cleavage of aza-bicyclo[3.2.2]nonene 14, which simultaneously generates the C2 and C5 substituents in a stereoselective manner.

The discovery and structure-activity relationships leading to CE-156811, a difluorophenyl cyclopropyl fluoroether: a novel potent antibacterial analog derived from hygromycin A.

SAR studies and optimization of various modified Hygromycin A fluoroalkyl ethers, which led to the discovery of the highly potent 4'-(2-cyclopropyl-2-fluoroethyl ether) antibacterial CE-156811 (1) derived from truncation of the ribose ring and difluorination of the phenyl found in Hygromycin A, are discussed.

Molecular features crucial to the activity of pyrimidine benzamide-based thrombopoietin receptor agonists.

The identification of small molecule modulators of biological processes mediated via protein-protein interactions has generally proved to be a challenging endeavor. In the case of the thrombopoietin receptor (TPOr), however, a number of small molecule types have been reported to display biological activity similar to that of the agonist protein TPO. Through a detailed analysis of structure-activity relationships, X-ray crystal structures, NMR coupling constants, nuclear Overhauser effects, and computational data, we have determined the agonism-inducing conformation of one series of small molecule TPOr agonists. The relationship of this agonism-inducing conformation to that of other series of TPO receptor agonists is discussed.

Solid-state characterization of an NR2B selective N-methyl d-aspartate (NMDA) antagonist polymorphs.

(-)-6-[2-[4-(3-Fluorophenyl)-4-hydroxy-piperidin-1-yl]-1-hydroxyethyl]-3,4-dihydro-quinolin-2(1H)-one (compound A) is an NR2B selective N-methyl d-aspartate (NMDA) antagonist that has shown at least two polymorphs, forms I and II. In this report, we prepared two polymorphs, forms I and II and their crystal forms were identified and characterized by single crystal X-ray diffractometry, differential scanning calorimetry (DSC) and variable temperature powder X-ray diffractometry (VT-PXRD). The results of DSC and VT-PXRD suggested that compound A has at least three polymorphic forms: I, II and a new form III, and that forms II and III showed an enantiotropic relationship. We also performed single crystal X-ray analyses of specific conditions based on the results of VT-PXRD. The unit cell dimensions in crystallographic parameter and molecular arrangements of form I were quite different from forms II and III. Whereas, the crystal structures of forms II and III were similar with the exception of the C58-C59-C61-C62 torsion angle.

2,6-Diisopropyl-anilinium chloride.

The title compound, C(12)H(20)N(+)·Cl(-), crystallizes with the chloride anions situated on twofold axes, while the cation is on a general position. All conventional hydrogen-bond donors and acceptors are utilized, forming a hydrogen-bonded ladder motif along the c axis. Investigation of the torsion angles between aromatic systems and isopropyl groups reveals unusual geometrical features. One isopropyl groups exhibits an expected eclipsed conformation with respect to the aromatic ring. The other isopropyl group shows a slight twist with respect to the aromatic ring. The short Cl⋯HC(methine) contact (2.88 Å) observed in the asymmetric unit is the probable reason for the twist feature around the isopropyl area.

Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design.

Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.

Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit.

The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail, and additional analogues with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays.

Twisted amide reduction under Wolff-Kishner conditions: synthesis of a benzo-1-aza-adamantane derivative.

A synthesis of 4,5-benzo-1-aza-tricyclo[4.3.1.1(3,8)]undecane (1), a benzo-1-aza-adamantane derivative, is described and features a previously unknown application of the Wolff-Kishner reduction of a nonresonance stabilized or "twisted" amide. An intermediate amino ester is converted to a severely "twisted amide", which, when exposed to hydrazine in alcohol, provides the corresponding "twisted" amino hydrazone. Wolff-Kishner conditions (KOH/ethylene glycol, 200 degrees C) provide the reduced target 1 without hydrolysis to amino acid derivatives. These operations are conveniently performed in a single flask in high yield.