Month: November 2022

Kosak, Urban published the artcileThe Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity, HPLC of Formula: 39546-32-2, the publication is Journal of Medicinal Chemistry (2018), 61(1), 119-139, database is CAplus and MEDLINE.

The enzymic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer’s disease, thus classifying BChE as a promising drug target in advanced Alzheimer’s disease. Structure-based drug discovery approaches to develop potent, selective and reversible human BChE inhibitors was used. The most potent, compound I, had a picomolar inhibition constant vs. BChE due to strong cation-π interactions, as revealed by the solved crystal structure of its complex with human BChE. Addnl., compound I inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that compound I is highly protein bound, highly permeable and metabolically stable. Finally, compound I crosses the blood-brain barrier, and it improves memory, cognitive functions and learning abilities of mice in a scopolamine model of dementia. Compound I is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer’s disease.

Journal of Medicinal Chemistry published new progress about 39546-32-2. 39546-32-2 belongs to piperidines, auxiliary class Piperidine,Amine,Amide, name is Piperidine-4-carboxamide, and the molecular formula is C6H12N2O, HPLC of Formula: 39546-32-2.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Kosak, Urban published the artcileDevelopment of an in-vivo active reversible butyrylcholinesterase inhibitor, HPLC of Formula: 39546-32-2, the publication is Scientific Reports (2016), 39495, database is CAplus and MEDLINE.

Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the mol. basis of its low nanomolar potency. Addnl., this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.

Scientific Reports published new progress about 39546-32-2. 39546-32-2 belongs to piperidines, auxiliary class Piperidine,Amine,Amide, name is Piperidine-4-carboxamide, and the molecular formula is C6H12N2O, HPLC of Formula: 39546-32-2.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Bellomo, Piero published the artcileSynthesis and antibacterial activity of some derivatives of tolypomycinone. Relation between structure and activity in ansamycins, COA of Formula: C7H16N2, the publication is Journal of Medicinal Chemistry (1977), 20(10), 1287-91, database is CAplus and MEDLINE.

A series of 29 3-aminotolypomycinone derivatives and 3,16-diamino-16,17-dihydrotolypomycinone derivatives were prepared by addition of a primary or secondary amine to tolypomycinone, and 3-(methylamino)-16,17-dihydrotolypomycinone was prepared by addition of MeNH₂ to 16,17-dihydrotolypomycinone. One of the most active compounds, 3-[2-(N-morpholyl)ethylamino]tolypomycinone (I), had enhanced stability and prolonged activity against Staphylococcus aureus in acid and alk. solutions as compared to tolypomycin Y. In vitro tests showed high antibacterial activity for several compounds against S. aureus and 3 strains of gram-neg. bacteria. Structure-activity relations are discussed.

Journal of Medicinal Chemistry published new progress about 14613-37-7. 14613-37-7 belongs to piperidines, auxiliary class Piperidine,Amine, name is (1-Methylpiperidin-3-yl)methanamine, and the molecular formula is C7H16N2, COA of Formula: C7H16N2.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Leadbetter, Elizabeth A. published the artcileNK T cells provide lipid antigen-specific cognate help for B cells, COA of Formula: C11H15NOS, the publication is Proceedings of the National Academy of Sciences of the United States of America (2008), 105(24), 8339-8344, database is CAplus and MEDLINE.

The mechanisms of T cell help for production of antilipid antibodies are largely unknown. This study shows that invariant NK T cells (iNK T cells) and B cells cooperate in a model of antilipid antigen-specific antibody responses. We use a model haptenated lipid mol., 4-hydroxy-3-nitrophenyl-αGalactosylCeramide (NP-αGalCer), to demonstrate that iNK T cells provide cognate help to lipid-antigen-presenting B cells. B cells proliferate and IgG anti-NP is produced from in vivo-immunized mice and in vitro cocultures of B and NK T cells after exposure to NP-αGalCer, but not closely related control glycolipids. This B cell response is absent in CD1d^-/- and Jα18^-/- mice but not CD4^-/- mice. The antibody response to NP-αGalCer is dominated by the IgM, IgG3, and IgG2c isotypes, and marginal zone B cells stimulate better in vitro lipid antigen-driven proliferation than follicular B cells, suggesting an important role for this B cell subset. iNK T cell help for B cells is shown to involve cognate help from CD1d-instructed lipid-specific iNK T cells, with help provided via CD40L, B7-1/B7-2, and IFN-γ, but not IL-4. This model provides evidence of iNK T cell help for antilipid antibody production, an important aspect of infections, autoimmune diseases, and vaccine development. Our findings also now allow prediction of those microbial antigens that would be expected to elicit cognate iNKT cell help for antibody production, namely those that can stimulate iNKT cells and at the same time have a polar moiety that can be recognized by antibodies.

Proceedings of the National Academy of Sciences of the United States of America published new progress about 4972-31-0. 4972-31-0 belongs to piperidines, auxiliary class Piperidine,Benzene, name is 1-(Phenylsulfinyl)piperidine, and the molecular formula is C11H15NOS, COA of Formula: C11H15NOS.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Gordon, Richard K. published the artcileDistance geometry of α-substituted 2,2-diphenylpropionate antimuscarinics, SDS of cas: 13444-24-1, the publication is Molecular Pharmacology (1989), 36(5), 766-72, database is CAplus and MEDLINE.

Quant. relationships between pharmacol. activities and phys. properties of a series of 2,2-diphenylpropionate compounds were used to define the topog. of the antagonist binding site of muscarinic receptors. XICAMM, a computer mol. modeling program, was used to calculate geometric and topol. values of the compounds The compounds were tested for their antimuscarinic activities by inhibition of [N-methyl-³H]scopolamine binding to the muscarinic receptors of N4TG1 neuroblastoma cells, by inhibition of carbachol-induced α-amylase release from rat pancreas acini, and by blocking acetylcholine-induced contraction of guinea pig ileum. To evaluate only the effect of the bond distance on the potency of the synthesized antimuscarinics, the compounds were designed to contain as many constant features as possible. Neither the hydrophobic nor the ester moieties of the compounds were changed, and the rings containing the protonated N saturated and restricted. The antimuscarinic activities obtained from the 3 assays correlated with each other, with the exception of 2 compounds The 2 compounds demonstrated specificity for the M3 muscarinic receptor subtype in the pancreas. The antimuscarinic activities were related to the bond distances between the carbonyl O (constant electroneg. locus) and the protonated N (center of cationic charge) of the 2,2-diphenylpropionate compounds Parabolic relationships between the pharmacol. activities and bond distances were empirically established. The shortest calculated bond distance of these compounds was ∼4.4 Å, whereas the longest was ∼5.9 Å. The maximum antimuscarinic potency was observed with a calculated bond distance of ∼5.2 Å in all 3 assays.

Molecular Pharmacology published new progress about 13444-24-1. 13444-24-1 belongs to piperidines, auxiliary class Piperidine,Alcohol, name is 1-Ethylpiperidin-3-ol, and the molecular formula is C7H15NO, SDS of cas: 13444-24-1.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Bataille, Carole J. R. published the artcileThiazolidine derivatives as potent and selective inhibitors of the PIM kinase family, Synthetic Route of 634905-21-8, the publication is Bioorganic & Medicinal Chemistry (2017), 25(9), 2657-2665, database is CAplus and MEDLINE.

The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematol. malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of mol. modeling and optimization studies, the intrinsic potencies and mol. properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC₅₀ of 0.75 μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition.

Bioorganic & Medicinal Chemistry published new progress about 634905-21-8. 634905-21-8 belongs to piperidines, auxiliary class Piperidine,Boronic acid and ester,Benzene,Boronic Acids,Boronic acid and ester, name is (3-(Piperidin-1-yl)phenyl)boronic acid, and the molecular formula is C11H16BNO2, Synthetic Route of 634905-21-8.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Owens, Timothy D. published the artcileDiscovery of Reversible Covalent Bruton′s Tyrosine Kinase Inhibitors PRN473 and PRN1008 (Rilzabrutinib), Quality Control of 1971920-73-6, the publication is Journal of Medicinal Chemistry (2022), 65(7), 5300-5316, database is CAplus and MEDLINE.

Bruton′s tyrosine kinase (BTK), a Tec family tyrosine kinase, is critical in immune pathways as an essential intracellular signaling element, participating in both adaptive and immune responses. Currently approved BTK inhibitors are irreversible covalent inhibitors and limited to oncol. indications. Herein, we describe the design of covalent reversible BTK inhibitors and the discoveries of PRN473 (11) and rilzabrutinib (PRN1008, 12). These compounds have exhibited potent and durable inhibition of BTK, in vivo efficacy in rodent arthritis models, and clin. efficacy in canine pemphigus foliaceus. Compound 11 has completed phase 1 trials as a topical agent, and 12 is in phase 3 trials for pemphigus vulgaris and immune thrombocytopenia.

Journal of Medicinal Chemistry published new progress about 1971920-73-6. 1971920-73-6 belongs to piperidines, auxiliary class Other Aliphatic Heterocyclic,Piperidine,Alkenyl,Amine,Benzene,Ether,Inhibitor,Inhibitor, name is (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, and the molecular formula is C26H25N5O3, Quality Control of 1971920-73-6.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Ball, Matthew published the artcileDevelopment of a Manufacturing Route to Avibactam, a β-Lactamase Inhibitor, Quality Control of 1416134-49-0, the publication is Organic Process Research & Development (2016), 20(10), 1799-1805, database is CAplus.

Process development work to provide an efficient, robust, and cost-effective manufacturing route to avibactam, a β-lactamase inhibitor is presented herewith. Aspects of this optimization work include the counterintuitive introduction of a protecting group to effect a difficult urea formation and the use of controlled feed hydrogenation conditions to facilitate an elegant one pot debenzylation and sulfation reaction. Overall, the com. process delivers avibactam in much improved yield with significant reduction in the environmental footprint.

Organic Process Research & Development published new progress about 1416134-49-0. 1416134-49-0 belongs to piperidines, auxiliary class Piperidine,Chiral,Amine,Benzene,Amide, name is (2S,5R)-5-((Benzyloxy)amino)piperidine-2-carboxamide, and the molecular formula is C13H19N3O2, Quality Control of 1416134-49-0.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Heald, Robert published the artcileNoncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study, Category: piperidines, the publication is Journal of Medicinal Chemistry (2015), 58(22), 8877-8895, database is CAplus and MEDLINE.

Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clin. responses only last for 8-14 mo. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.

Journal of Medicinal Chemistry published new progress about 39546-32-2. 39546-32-2 belongs to piperidines, auxiliary class Piperidine,Amine,Amide, name is Piperidine-4-carboxamide, and the molecular formula is C6H12N2O, Category: piperidines.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem

Marchand-Brynaert, Jacqueline published the artcileDesign and Synthesis of Functionalized Oxaziridines as Topological Analogs of Penicillins, Product Details of C19H21N, the publication is Israel Journal of Chemistry (2013), 29(2-3), 247-255, database is CAplus.

Oxaziridines were examined as potential alkylating inhibitors of bacterial serine D,D-peptidases. Structures were designed to mimic known β-lactam antibiotics taking into account stereoelectronic requirements for a nucleophilic attack on a three-membered ring. Novel oxaziridines equipped with functionalized side chains were prepared They showed poor antibacterial activities in vitro, perhaps as a result of their low chem. stability.

Israel Journal of Chemistry published new progress about 35661-58-6. 35661-58-6 belongs to piperidines, auxiliary class Piperidine,Benzene, name is 1-((9H-Fluoren-9-yl)methyl)piperidine, and the molecular formula is C19H21N, Product Details of C19H21N.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem