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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Cobimetinib (CotellicTM) (Figure 6.51) is a MEK inhibitor developed by Exelixis and Genentech (Roche). It is used in combination with the B-RAF inhibitor vemurafenib (ZelborafTM) to treat melanoma. The structure is unusual in containing a four-membered azetidine ring and four halogen atoms. Structure of cobimetinib (CotellicTM).
Developmental Aspects of the Alveolar Epithelium and the Pulmonary Surfactant System
Published in Jacques R. Bourbon, Pulmonary Surfactant: Biochemical, Functional, Regulatory, and Clinical Concepts, 2019
Jacques R. Bourbon, Caroline Fraslon
Experiments have been undertaken in order to disturb the formation of the basement membrane in developing lung in vivo or in in vitro models of lung organogenesis and to evaluate the consequences on epithelial differentiation and maturation. One approach consisted of perturbing collagen synthesis with the aid of amino acid analogs of proline, an amino acid particularly abundant in collagen. In vitro, l-azetidine-2-carboxylic acid (LACA) and α,α′-dipyridyl deeply perturbed branching morphogenesis of mouse lung rudiments, although cell and tissue integrity was not affected.97 The administration of LACA to rat fetuses retarded lung growth and surfactant biosynthesis.98 This result, however, must be interpreted with caution. The delay in surfactant synthesis could effectively be a consequence of impairment of ECM biosynthesis and alteration of the modulation of epithelial maturation by the basement membrane. However, it can also result from impairments in the production of various proline-containing proteins other than collagens, including a number of enzymes and surfactant protein A (SP-A), which is known to contain a collagen-like domain (see Chapter 4).
The putA GEne Product: Two Enzymatic Activities and a Regulatory Function in a Single Polypeptide
Published in James F. Kane, Multifunctional Proteins: Catalytic/Structural and Regulatory, 2019
Mutations that affect the enzyme activities of the putA gene product show two phenotypes with respect to the regulation of the putP gene. Wild type cells are sensitive to the proline analogue azetidine carboxylic acid (AZTS). Mutants defective for the putP gene are resistant to AZT. Mutants constitutive for both the expression of proline oxidase and proline permease show a heightened sensitivity to AZT (AZTSS phenotype).12 Mutants lacking proline oxidase activity may be either sensitive to AZT at a level similar to that of wild type cells (AZTS) or demonstrate a heightened sensitivity (AZTSS) similar to that of mutants constitutive for the expression of the put genes. The putA− mutants which are AZTSS were shown to have lost their ability to regulate the permease.12 They behave like constitutive mutants for the putP gene. All insertion and amber mutants in the putA gene are in the AZTSS class.
Monocyclic beta–lactams for therapeutic uses: a patent overview (2010–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Katarina Grabrijan, Nika Strašek, Stanislav Gobec
Recently, the interest in monocyclic beta-lactams for pharmaceutical development has increased again. In the last decade, monocyclic beta-lactams have been reborn as antibacterials, because they are effective against multidrug-resistant bacteria and stable against beta-lactamases. The majority of patents published in that period cover the previously known biological effects of substituted 2-azetidines with improved activity as antibacterial agents, cholesterol absorption inhibitors and vasopressin V1a antagonists. But other patents have also been filed describing completely new pharmacological activities of monocyclic beta-lactams as activators and inhibitors of lecithin cholesterol acyltransferase, factor XIa or kallikrein inhibitors, N-acylethanolamine acid amidase inhibitors, beta-lactam combretastatin mimics, RORγt (retinoid-related orphan receptor gamma t) modulators, and modulators of glutamate uptake, all of which are discussed below.
Trace amine associated receptor 1 (TAAR1) modulators: a patent review (2010-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Michele Tonelli, Elena Cichero
The morpholine nucleus has been also simplified, considering the ring-contracted azetidine scaffold as basic feature (Figure 4(f)) [40], whilst the oxygen atom has been carried out of the cycle, but respecting the same spatial distance between the two heteroatoms, likewise observable in the morpholine ring. Sometimes the O bridge atom has been isosterically substituted, varying the lipophilicity (S, NH, and CH2) and the flexibility (HC=) of the molecules, leading in all the cases to promising TAAR1 ligands. Indeed, the most potent and unselective TAAR1 targeting derivatives have been those bridged with the polar O atom, thus confirming its relevant role for the activity as played in the morpholine ring. Additionally, the simpler aryl azetidine scaffold has been still found able to bind to both the rodent receptors, even if at lower extent since the Ki values have undergone a significant increase to micromolar range. The recurrent motif composed of carboxamido or ureido spacers has allowed again the achievement of the optimal distance between the basic and lipophilic pharmacophoric units that mark all the TAAR1 ligands.
Selective estrogen receptor degraders (SERDs) and covalent antagonists (SERCAs): a patent review (2015-present)
Published in Expert Opinion on Therapeutic Patents, 2022
James S. Scott, Bernard Barlaam
A patent focussed on the in vitro antiproliferation activity of OP-1074 48 in combination with various chemotherapeutic agents was published by Olema pharmaceuticals in collaboration with Pfizer (Figure 20)[116]. A subsequent medicinal chemistry publication detailed the pharmacology of the compound (IC50 3.2 nM) and demonstrated regression in an MCF-7 xenograft model when dosed orally at 100 mg/kg[117]. In addition, a structural biology investigation as to how subtle changes in structure led to different pharmacology implicated the dynamics of helix 12 of the protein as a key component. A subsequent filing from the same inventors but attributed to Pfizer, detailed 20 related compounds with a cyclic azetidine base[118]. Example 105 49 was reported as a potent degrader of the estrogen receptor (IC50 4 nM). In 2017, a patent containing two compounds was reported with overlapping inventors but attributed to Olema pharmaceuticals[119]. Example B 50 was reported as a potent degrader of the estrogen receptor (IC50 2.8 nM) with in vivo activity at 10 mg/kg in an MCF-7 xenograft model. Comparative data with closely related chemical equity from the Genentech filing (Examples 102 and 107) was included to highlight differences in human protein binding and murine exposure. A more recent patent application [120] focussed on this compound with data showing good exposure in mouse, rat, dog, and monkey. Additional data relating to exposure in brain and in vivo activity as both single agent (1–10 mg/kg) and in combination with palbociclib were included. Olema have a compound (OP-1250) currently in development and, whilst the structure has not been formally disclosed at the time of writing, 50 is undoubtedly a compound of significant interest.