Structure-Based and Property-Driven Optimization of N-Aryl Imidazoles toward Potent and Selective Oral RORγt Inhibitors

Abstract

Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is considered to be the master transcription factor for the development of Th17 cells that produce proinflammatory cytokines such as IL-17A. Overproportionate Th17 cell abundance is associated with the pathogenesis of many inflammatory conditions including psoriasis. In a high-throughput fluorescence resonance energy transfer (FRET) screen, we identified compound 1 as a hit with promising lipophilic efficiency (LipE). Using structure-based drug design based on a number of X-ray cocrystal structures, we morphed this hit class into potent imidazoles, exemplified by compound 3. To improve the poor absorption, distribution, metabolism, and excretion (ADME) properties of neutral imidazoles, we extended our ligands with carboxylic acid substituents toward a polar, water-rich area of the protein. This highly lipophilicity-efficient modification ultimately led to the discovery of compound 14, a potent and selective inhibitor of RORγt with good ADME properties and excellent in vivo pharmacokinetics. This compound showed good efficacy in an in vivo delayed-type hypersensitivity pharmacology model in rats.

AZD0284, a Potent, Selective, and Orally Bioavailable Inverse Agonist of Retinoic Acid Receptor-Related Orphan Receptor C2

“…The large and mainly hydrophobic ligand-binding pocket (LBP) presents a challenge for the development of orally bioavailable small molecules. − Despite these difficulties, several orthosteric modulators with good pharmacokinetic properties for either oral or topical applications have been described. − Several of these molecules have also progressed into clinical trials, with one of them, VPT-43742, showing efficacy in psoriasis patients after oral administration over 4 weeks. − Recently, two classes of allosteric modulators, binding outside the canonical pocket of RORC2 have also been disclosed. − …”

“…The introduction of groups such as cyclopropylmethylene (27) or cyclopropylamino (31) led to a 3-to 4-fold increase in cell potency, but that change also led to a very strong increase in CYP2D6 inhibition (Table 4). A methoxyethyl (24), cyclopropyl (26), or methylamino (30) group kept cell potency at levels similar to 18, but these derivatives either showed higher intrinsic clearance values (24), or were more potent inhibitors of CYP2D6, and thus offered no advantage compared to the methyl group. Changing the methyl to a 2-hydroxyethyl group, as in 25, lowered log D further, but also led to a 3-fold loss in cell potency.…”

Image2SMILES: Transformer‐Based Molecular Optical Recognition Engine**

“…So manual test is feasible, but for a limited number of samples. We took ten articles [34][35][36][37][38][39][40][41][42][43] to test our method on the real data. Structures that represent reaction mechanisms were excluded, so we regarded only molecules and Markush templates.…”

Image2SMILES: Transformer-based Molecular Optical Recognition Engine

“…So manual test is feasible, but for a limited number of samples. We took ten articles [28][29][30][31][32][33][34][35][36][37] to test our method on the real data. Structures that represent reaction mechanisms were excluded, so we regarded only molecules and Markush templates.…”