Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis

Abstract

With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL-23-induced mouse skin inflammation model.

Intrinsic Property Forecast Index (iPFI) as a Rule of Thumb for Medicinal Chemists to Remove a Phototoxicity Liability

“…For example, of the three pyridine/ oxetane matched pairs resulting in no change in phototoxicity potential, two have starting points that are already nonphototoxic, while the last one, which is phototoxic, bears a phototoxicophore. 12 Furthermore, of the 4789 matched pairs giving a negative ΔiPFI, only 335 give rise to an increase in phototoxicity potential while almost four times as much (1311) instead give rise to a decrease (or 10 times as much fold-difference with ΔiPFI ≤ −1).…”

“…It should be noted that an iPFI reduction is only likely to produce a phototoxicity potential reduction if at least a low risk exists, it occurs between iPFI values where the proportion of phototoxic compounds changes significantly and if no specific phototoxicity-causing substructural elements are involved. For example, of the three pyridine/oxetane matched pairs resulting in no change in phototoxicity potential, two have starting points that are already nonphototoxic, while the last one, which is phototoxic, bears a phototoxicophore …”

Sulfoximines as Rising Stars in Modern Drug Discovery? Current Status and Perspective on an Emerging Functional Group in Medicinal Chemistry

“…To identify a novel inverse agonist of RORγ with well-balanced log D (which is linked to improved skin penetration and lowered systemic exposure), researchers at Nestlé Skin Health selected 100 as a starting point for their drug discovery program. During the development of another potent inverse agonist of RORγ, CD12681, the studies at Nestlé Skin Health realized that alternative substituents at the sulfonamide nitrogen other than isobutyl and 4-(ethyl)­phenyl failed to retain potency . The des-hydroxymethyl analogue showed a 23-fold lower activity (IC 50 (RORγ-GAL4 cell) = 390 nM) than that of its counterpart; hence, the hydroxymethyl group was assumed to be pivotal for hydrophilic interactions with the RORγ ligand-binding domain (cf.…”

“…Table 12, Supporting Information). However, the identification of suitable replacements for this group was proposed. , Replacement of the hydroxymethyl moiety with sulfur moieties, such as sulfoxide, sulfone, and sulfonamide, led to analogues with decreased potency and/or lowered lipophilic ligand efficiency (LipE, detailed values are shown in Table 12, Supporting Information). The impact of lipophilic ligand efficiency was excellently reviewed elsewhere .…”

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. − …”