Pierre Deprez

Discovery and Optimization of an Azetidine Chemical Series As a Free Fatty Acid Receptor 2 (FFA2) Antagonist: From Hit to Clinic

FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid 99 (GLPG0974), is able to inhibit acetate-induced neutrophil migration strongly in vitro and demonstrated ability to inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific epitope [AE], in a human whole blood assay. All together, these data supported the progression of 99 toward next phases, becoming the first FFA2 antagonist to reach the clinic.

Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634

Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the compound library was screened against JAK1, resulting in the identification of a triazolopyridine-based series of inhibitors represented by 3. Optimization within this chemical series led to identification of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA and phase 2A development for Crohns disease (CD).

Discovery of Diarylhydantoins as New Selective Androgen Receptor Modulators

A novel selective androgen receptor modulator scaffold has been discovered through structural modifications of hydantoin antiandrogens. Several 4-(4-hydroxyphenyl)-N-arylhydantoins displayed partial agonism with nanomolar in vitro potency in transactivation experiments using androgen receptor (AR) transfected cells. In a standard castrated male rat model, several compounds showed good anabolic activity on levator ani muscle, dissociated from the androgenic activity on ventral prostate, after oral dosing at 30 mg/kg. (+)-4-[3,4-Dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile ((+)-11b) displayed anabolic potency with a strong dissociation between levator ani muscle and ventral prostate (A(50) = 0.5 mg/kg vs 70 mg/kg). The binding modes of two compounds, including (+)-11b, within the AR ligand-binding domain have been studied by cocrystallization experiments using a coactivator-like peptide. Both compounds bound to the same site, and the overall structures of the AR were very similar.

Identification of a 4-(Hydroxymethyl)diarylhydantoin as a Selective Androgen Receptor Modulator

Structural modification performed on a 4-methyl-4-(4-hydroxyphenyl)hydantoin series is described which resulted in the development of a new series of 4-(hydroxymethyl)diarylhydantoin analogues as potent, partial agonists of the human androgen receptor. This led to the identification of (S)-(-)-4-(4-(hydroxymethyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile ((S)-(-)-18a, GLPG0492) evaluated in vivo in a classical model of orchidectomized rat. In this model, (-)-18a exhibited anabolic activity on muscle, strongly dissociated from the androgenic activity on prostate after oral dosing. (-)-18a has very good pharmacokinetic properties, including bioavailability in rat (F > 50%), and is currently under evaluation in phase I clinical trials.

Synthesis of difluoromethylthio imidazole from methylthio imidazole

Abstract Demethylation of methylthio imidazole 1 via a Pummerer rearrangement onto the corresponding sulfoxide 2 afforded imidazole thiol 4 which was then difluoromethylated with the sodium chlorodifluoroacetate/NaI system in 71% overall yield.

New potent calcimimetics: II. Discovery of benzothiazole trisubstituted ureas.

Following the identification of trisubstituted ureas as a promising new chemical series of allosteric modulators of the calcium sensing receptor (CaSR), we further explored the SAR around the urea substitution, leading to the discovery of benzothiazole urea compound 13. This compound is a potent calcimimetic with an EC50=20 nM (luciferase assay). Evaluated in an in vivo model of chronic renal failure (short term and long term in 5/6 nephrectomized rats), benzothiazole urea 13 significantly decreased PTH levels after oral administration while keeping calcemia within the normal range.

Discovery of Thioazepinone Ligands for Src SH2: From Non-specific to Specific Binding

The structure-based design and synthesis of new thioazepinones as ligands for Src SH2 protein is presented. From benzothioazepinones, ligands with somewhat unspecific binding properties, simpler thioazepinones were designed, the best ones demonstrated nanomolar affinity for Src SH2. A few of these new ligands were crystallized with the protein and demonstrated a specific binding mode with the protein.

Balanced AT1 and AT2 angiotensin II antagonists. I. New orally active 5-carboxyl imidazolyl biphenyl sulfonylureas

Abstract A series of substituted imidazolyl biphenyl sulfonylureas have been synthesized. Substitution on the imidazole ring but essentially on the urea side chain significantly increased AT2 binding with cyclohexylmethyl, cyclopentylmethyl and benzyl as the most effective substituents. Imidazole 13d, as a representative member of this series, displayed nanomolar binding affinity for both the AT1 and AT2 angiotensin II receptor subtypes as well as oral activity.

Efficient Two-Step Syntheses of Sulfonylguanidines from Sulfonamides

Abstract Various sulfonylguanidines have been synthesized from a sulfonamide by two mild and efficient synthetic methods. In route A, the methylthio group of S-methylsulfonylisothiourea is displaced by a variety of amines while in route B the amines are reacted with sulfonylthiourea in the presence of mercury oxide HgO.

Balanced AT1 and AT2 angiotensin II antagonists. III. potent and orally active 5-β-ketosulfoxide imidazolyl biphenyl sulfonylureas

Abstract In the imidazolyl biphenyl sulfonylurea series, effects of substitution in position 5 of the imidazole ring with enolic ketone moiety were studied on AT 2 binding. β-ketosulfoxide, β-ketosulfone and β-ketoester proved to be highly effective substituents for potent nanomolar binding affinity on both AT 1 and AT 2 receptor subtypes. This led to the identification of β-ketophenylsulfoxide RU 64276 as a potent and orally active AT 1 antagonist and AT 2 binding inhibitor.