Christian Montalbetti

A CONVERGENT SYNTHESIS OF FUNCTIONALIZED B-SECO TAXANE SKELETONS

Abstract The sequential Sonogashira cross-coupling reactions with water soluble and anhydrous Pd(0) catalysts between vinylic iodo derivatives 6, 8 and 3-iodocyclohexe none 7 with trimethyl silyl acetylene are used to produce functionalized intermediates 11 and 18. Conjugate addition followed by enolate trapping with trimethyl orthoformate provided B-seco taxane derivatives 14 and 20.

Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K)

We report here structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical NF-κB1 (REL-A/p50).

Conformational analysis of (R,S)-4-amido-2,4-dimethyl-butyric acid derivatives

NMR spectra of various N-acyl derivatives of (R,S)-4-amino-2,4-dimethyl-butyric acid show these compounds to be biconformational, populating the conformers 4 and 5 of the molecular backbone. Both predominant conformers have the amide group gauche to the main chain.

Remote substituent control of the regioselectivity of the aryl- and vinylpalladation of 7-oxabicyclo[2.2.1]heptenes

Pd-catalyzed arylations of 2-exo-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl acetate and 7-oxabicycio[2.2.1]hept-5-en-2-one are regio- and stereoselective giving products of H-2(HCOOH) and Me(3)SiC=H coupling in which the aryl group (4-MeOC(6)H(4)) prefers the exo position of C(5) whereas the Pd-catatyzed vinylations with methyl-2-iodoacrylate prefers the exo position of C(6) center.

Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK).

Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.

The synthesis and evaluation of indolylureas as PKCα inhibitors

PKCα and PKA have crucial but opposing roles in the regulation of calcium handling within myocytes. Identification of compounds that inhibit PKCα, but not PKA, are potential therapeutic targets for the treatment of heart disease. The synthesis of indolylureas are described, and a compound displaying nanomolar inhibition towards PKCα with significant selectivity over PKA has been identified.

Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK).

Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.

Design, Synthesis, and Evaluation of a Novel Series of Indole Sulfonamide Peroxisome Proliferator Activated Receptor (PPAR) α/γ/δ Triple Activators: Discovery of Lanifibranor, a New Antifibrotic Clinical Candidate

Here, we describe the identification and synthesis of novel indole sulfonamide derivatives that activate the three peroxisome proliferator activated receptor (PPAR) isoforms. Starting with a PPARα activator, compound 4, identified during a high throughput screening (HTS) of our proprietary screening library, a systematic optimization led to the discovery of lanifibranor (IVA337) 5, a moderately potent and well balanced pan PPAR agonist with an excellent safety profile. In vitro and in vivo, compound 5 demonstrated strong activity in models that are relevant to nonalcoholic steatohepatitis (NASH) pathophysiology suggesting therapeutic potential for NASH patients.