Chulho Choi

Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.

P2Y1 receptor antagonists as novel antithrombotic agents.

The P2Y(1) and P2Y(12) purinergic receptors are responsible for mediating adenosine diphosphate (ADP) dependent platelet aggregation. Evidence from P2Y(1) knockout studies as well as from nucleotide-based small molecule P2Y(1) antagonists has suggested that the antagonism of this receptor may offer a novel and effective method for the treatment of thrombotic disorders. Herein, we report the identification and optimization of a series of non-nucleotide P2Y(1) antagonists that are potent and orally bioavailable.

Design and evaluation of a 2-(2,3,6-trifluorophenyl)acetamide derivative as an agonist of the GPR119 receptor.

The design and synthesis of a GPR119 agonist bearing a 2-(2,3,6-trifluorophenyl)acetamide group is described. The design capitalized on the conformational restriction found in N-β-fluoroethylamide derivatives to help maintain good levels of potency while driving down both lipophilicity and oxidative metabolism in human liver microsomes. The chemical stability and bioactivation potential are discussed.

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.

Aminocarbonylation of aryl tosylates to carboxamides.

The palladium - catalyzed aminocarbonylation of aryl tosylates with amines is reported. Suitable conditions were identified by high throughput reaction screening and then further optimized. The substrate scope of the reaction with respect to the aryl tosylate component and the amine component are reported. Competitive aminolysis of the aryl tosylates to afford the amine toluenesulfonamides and the phenol was not observed.

Selectively targeting an inactive conformation of interleukin-2-inducible T-cell kinase by allosteric inhibitors

ITK (interleukin-2-inducible T-cell kinase) is a critical component of signal transduction in T-cells and has a well-validated role in their proliferation, cytokine release and chemotaxis. ITK is an attractive target for the treatment of T-cell-mediated inflammatory diseases. In the present study we describe the discovery of kinase inhibitors that preferentially bind to an allosteric pocket of ITK. The novel ITK allosteric site was characterized by NMR, surface plasmon resonance, isothermal titration calorimetry, enzymology and X-ray crystallography. Initial screening hits bound to both the allosteric pocket and the ATP site. Successful lead optimization was achieved by improving the contribution of the allosteric component to the overall inhibition. NMR competition experiments demonstrated that the dual-site binders showed higher affinity for the allosteric site compared with the ATP site. Moreover, an optimized inhibitor displayed non-competitive inhibition with respect to ATP as shown by steady-state enzyme kinetics. The activity of the isolated kinase domain and auto-activation of the full-length enzyme were inhibited with similar potency. However, inhibition of the activated full-length enzyme was weaker, presumably because the allosteric site is altered when ITK becomes activated. An optimized lead showed exquisite kinome selectivity and is efficacious in human whole blood and proximal cell-based assays.

Structurally Divergent Lithium Catalyzed Friedel-Crafts Reactions on Oxetan-3-ols: Synthesis of 3,3-Diaryloxetanes and 2,3-Dihydrobenzofurans.

Abstract The first examples of 3,3‐diaryloxetanes are prepared in a lithium‐catalyzed and substrate dependent divergent Friedel–Crafts reaction. para‐Selective Friedel–Crafts reactions of phenols using oxetan‐3‐ols afford 3,3‐diaryloxetanes by displacement of the hydroxy group. These constitute new isosteres for benzophenones and diarylmethanes. Conversely, ortho‐selective Friedel–Crafts reactions of phenols afford 3‐aryl‐3‐hydroxymethyl‐dihydrobenzofurans by tandem alkylation–ring‐opening reactions; the outcome of the reaction diverging to structurally distinct products dependent on the substrate regioselectivity. Further reactivity of the oxetane products is demonstrated, suitable for incorporation into drug discovery efforts.

Reversal of Diastereoselection in the Conjugate Addition of Cuprates to Unsaturated Lactams.

We report that the stereochemical outcome of the conjugate addition of organocopper reagents to bicyclic α,β-unsaturated lactams derived from pyroglutaminol is determined by the nature of the aminal group. Bicyclic α,β-unsaturated lactams in which the aminal is derived from a ketone have been found to afford products of syn conjugate addition. By contrast, bicyclic α,β-unsaturated lactams in which the aminal is derived from an aldehyde afford products of anti conjugate addition. These remarkably different results obtained from very similar starting materials are unexpected.

Manganese‐Based Photoredox Catalysis for C‐H Alkylation of Heteroarenes: Applications and Mechanistic Studies

A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn2 (CO)10 , to generate alkyl radicals from alkyl iodides has been developed. This Minisci protocol is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert-butyl carbamates (Boc-group), cyclobutanes, and spirocycles. The robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs. Photophysical and DFT studies indicate a light-initiated chain reaction mechanism propagated by . Mn(CO)5 . The rate-limiting step is the iodine abstraction from an alkyl iodide by . Mn(CO)5 .

Lithium-Catalyzed Thiol Alkylation with Tertiary and Secondary Alcohols: Synthesis of 3-Sulfanyl-Oxetanes as Bioisosteres

Abstract 3‐Sulfanyl‐oxetanes are presented as promising novel bioisosteric replacements for thioesters or benzyl sulfides. From oxetan‐3‐ols, a mild and inexpensive Li catalyst enables chemoselective C−OH activation and thiol alkylation. Oxetane sulfides are formed from various thiols providing novel motifs in new chemical space and specifically as bioisosteres for thioesters due to their similar shape and electronic properties. Under the same conditions, various π‐activated secondary and tertiary alcohols are also successful. Derivatization of the oxetane sulfide linker provides further novel oxetane classes and building blocks. Comparisons of key physicochemical properties of the oxetane compounds to selected carbonyl and methylene analogues indicate that these motifs are suitable for incorporation into drug discovery efforts.