Day: October 18, 2022

Miah, Afjal H.; Smith, Ian E. D.; Rackham, Mark; Mares, Alina; Thawani, Aditya R.; Nagilla, Rakesh; Haile, Pamela A.; Votta, Bartholomew J.; Gordon, Laurie J.; Watt, Gillian; Denyer, Jane; Fisher, Don T.; Dace, Phoebe; Giffen, Paul; Goncalves, Andrea; Churcher, Ian; Scott-Stevens, Paul; Harling, John D. published the artcile< Optimization of a Series of RIPK2 PROTACs>, Synthetic Route of 89793-12-4, the main research area is PROTAC RIPK2 IAP binder drug optimization.

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogs with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 mo duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.

Journal of Medicinal Chemistry published new progress about Blood. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Synthetic Route of 89793-12-4.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Rabal, Obdulia; Sanchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; de Miguel, Irene; Perez-Gonzalez, Marta; Garcia-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso de Mendoza, Ander; Saez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen published the artcile< Discovery of in Vivo Chemical Probes for Treating Alzheimer's Disease: Dual Phosphodiesterase 5 (PDE5) and Class I Histone Deacetylase Selective Inhibitors>, Name: Ethyl 2-chloropyrimidine-5-carboxylate, the main research area is sildenafil vardenafil orthoaminoanilide synthesis antiAlzheimer SAR PDE5 histone deacetylase; Alzheimer’s disease; PDE5 inhibition; chemical probes; class I HDAC selective inhibition; dual inhibitors; in vivo test.

In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer’s disease (AD), we have designed, synthesized, and tested novel chem. probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these mols. exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chem. series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biol. responses. The lead identification process led to compound I, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chem. probe; thus, I has been assayed in a mouse model of AD (Tg2576).

ACS Chemical Neuroscience published new progress about Alzheimer disease. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Name: Ethyl 2-chloropyrimidine-5-carboxylate.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia