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.

Complete 1 H, 13 C, and 15 N assignments of the minor isomer of codeine N-oxide.

Codeine N-oxide 2 is an active metabolite of codeine obtained by oxidation and observed as a degradant in codeine drug products such as syrups. Oxidation of codeine's N-methyl function can deliver two regio-isomers due to chirality of the tetra-substituted nitrogen. Hydrogen peroxide oxidation of codeine was performed and induced two different isomers in a 9:1 ratio; these isomers were isolated using preparative high performance liquid chromatography (HPLC) and fully characterized by nuclear magnetic resonance (NMR) techniques. We describe the complete assignment of the minor isomer of codeine N-oxide 3 and attribute a (S) configuration (N-methyl axial) of the tetra-substituted nitrogen. The effects of N-oxidation on the 15 N chemical shifts of the codeine are presented. The 15 N shifts were determined using the CIGAR-HMBC experiment at natural abundance, and the nitrogen resonance of codeine shifted downfield from 42.8 to 118.7 ppm for both N-oxide isomers.

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.

Discovery and process development of a novel TACE inhibitor for the topical treatment of psoriasis.

Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.

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.