Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature.

In our hands, efficient access to the 4-amino-3-carboxamide disubstituted pyridine-2(1H)-one kinase hinge-binder motif proved to be more challenging than anticipated requiring a significant investment in route scouting and optimization. This full paper focuses on the synthesis issues that we encountered during our route exploration and the original solutions we found that helped us to identify two optimized library-style processes to prepare our large kinase inhibitor library.

Structure-based design of Trifarotene (CD5789), a potent and selective RARγ agonist for the treatment of acne.

Retinoids have a dominant role in topical acne therapy and to date, only RARß and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known γ-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789.

Identification of novel TACE inhibitors compatible with topical application.

Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.

Identification of unknown impurities J, RRT 2.2, 2.4, 2.6 and 3.4 in tetralysal® capsules.

Tetralysal® is a Galderma oral drug product (DP) marketed for the treatment of acne. Tetralysal® is sold in capsules containing either 150 mg or 300 mg of the drug substance. In the British Pharmacopoeia monograph for Lymecycline Capsules, the impurities already specified in the drug substance (A-G), visible in the European Pharmacopoeia 〈1654〉, are also specified together with an unidentified impurity at RRT 1.6 (Impurity J). Based on both monographs Galderma has focused on characterizing most of specified and unspecified impurities to better understand the stability and degradation processes of the formulation. In this manuscript, through both formal synthesis, preparative LCMS and formal degradation studies, we are the first group to confirm the structural identities of 5 unidentified impurities (Impurity J (RRT 1.6), RRT 2.2, 2.4, 2.6 and 3.4), conditions which exacerbate the formation of all 5 impurities and response factors for RRT 2.2, 2.6 and 3.4.

Completion of the impurity profile of lymecycline: Formal identification of impurities E and F.

Lymecycline is the drug substance (DS) used in the Galderma drug product Tetralysal® capsules with 7 impurities currently described in the pharmacopeia labelled as A-G. In the current monograph, the structural identity of all impurities except E and F have been formally identified. In this manuscript, through both formal synthesis and preparative chromatography, we are the first group to confirm the structural identity, response factor of Impurity F and conditions which exacerbate the formation of both impurities.

Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne.

The use of an interleukin ß antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1ß into active IL-1ß, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.