¹ Discovery and process development of a novel TACE inhibitor for the topical treatment of psoriasis

Bioorg. Med. Chem. 2018, 26, 945-956

Although a first TACE inhibitor had already reached the clinic, researchers at Nestlé Skin Health/Galderma worked on a back-up program to identify structurally distinct candidates. In this news series, one of the main objectives was to improve solubility in PG/EtOH.

These efforts led to the identification of compound 1, a potent and soluble TACE inhibitor with robust activity in an oxazolone-induced chronic skin inflammation model.

² Macrocyclic Peptides as Drug Candidates: Recent Progress and Remaining Challenges

J. Am. Chem. Soc. 2019, 141, 4167−4181

In general, peptides are not readily absorbed by the gastrointestinal tract into the bloodstream. However, there are remarkable exceptions, like Cyclosporin A (CSA) which is used in clinic as an orally bioavailable immunosuppressant. This peptide is able to passively diffuse through biological membranes in part thanks the presence of hydrophobic side chains like in many other orally available peptides.

Moreover, it is believed that, analogously to the benefits for binding, a degree of conformational constraint and functional group preorganization is a prerequisite for passive diffusion across biological membranes: α,α-disubstituted amino acids are then suggested as a means to improve bioavailability.

³ Glucopyranosyl derivative and use thereof

WO2019/144864

The patent describes new SGLTs inhibitors, especially compounds with excellent inhibitory activities of SGLT1, having good development prospects as novel therapeutic drugs for diabetes.

^4a Heterocyclic Prolinamide Derivatives

WO2017222915

^4b Carbocyclic Prolinamide Derivatives

WO2017222914

The inventions disclose new potent nanomolar heterocyclic prolinamide derivatives for preventing and treating age-related macular degeneration (AMD) and related diseases of the eye.

The building blocks E were prepared in 5 steps from the chemical precursors A

⁵ 2-(2-Azabicyclo[3.1.0]hexan-1-yl)-1H-benzimidazole Derivatives

WO2020007964

The invention discloses the preparation of novel 2-(2-azabicyclo[3.1 .0]hexan-1-yl)-1 H-benzimidazole derivatives and their use as orexin receptor antagonists.

The constrained Boc proline derivative 1 enables the synthesis of an unprecedented chemical series. Compounds have antagonistic activities on both Ox1 and Ox2 receptors.

⁶ Structure-Based Design of Non-natural Macrocyclic Peptides That Inhibit Protein−Protein Interactions

J. Med. Chem. Soc. 2017, 60, 8982-8988

The field of constrained peptides is encountering a period of tremendous growth, largely fueled by the need to target protein-protein interactions.

A virtual library containing more than 1400 structures was screened against the target focusing on docking poses with the core structure resembling a known bioactive conformation.

The combination of the two highest affinity variations, a hydrophobic and a hydrophilic non-natural amino acid, allowed the design of a peptide with ca. 3-fold increased affinity for the target.

The finally evolved macrocyclic PPI inhibitor shows increased potency in PPI inhibition and in a cell-based assay.

⁷ Macrocyclic Peptides as Drug Candidates: Recent Progress and Remaining Challenges

J. Am. Chem. Soc. 2019, 141, 4167-4181

Structural features conferring resistance to proteolysis are fairly well-understood, and thus fine-tuning proteolytic stability of a peptide is arguably easier than modulating its other pharmacological properties.

Introducing any nonproteogenic elements into the structure of a peptide will render it more resistant to proteolysis.

Degarelixm, an FDA approved drug used in the treatment of prostate cancer, is a synthetic linear decapeptide containing six amino acids with nonproteogenic side chains. The peptide demonstrates an extraordinary long plasma circulation time (t_1/2 ~ 40-70 days).

⁸ Unusual amino acids in Medicinal Chemistry

J. Med Chem. 2016, 59, 24, 10807-10836

The α-disubstitution can be combined with cyclisation of the side chains to form cyclic amino acids. This conformationally restricted mino acids are frequently used as core components of bioactive molecules.

For example, aminocyclobutane-1-carbxylic acid anchors the HCV NS5A polymerase inhibitor 1 (BILB1941), the first allosteric non-nucleoside inhibitor of its class to reach the clinic.

Clinical candidate 2 (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases that inhibits tumor growth in a breast cancer xenograft model, is based around a piperidine-4-amino-4-carboxylic acid central residue. The same amino acid forms the core structure of opioid agonists 3 (Carfentanil) useful as anaesthetics