Rhodium-Catalyzed Synthesis of Branched Amines by Direct Addition of Benzamides to Imines

Rhodium-catalyzed addition of benzamide C–H bonds to a range of aromatic <i>N</i>-sulfonyl aldimines has been developed and proceeds with high functional group compatibility. The synthetic utility of the resulting branched amine products has also been demonstrated by the preparation of isoindoline and isoindolinone frameworks

Expedient Synthesis of α‑Heteroaryl Piperidines Using a Pd‑Catalyzed Suzuki Cross-Coupling–Reduction Sequence

A method for the modular synthesis of α-heteroaryl piperidines is reported. The two-step procedure consists of an initial Pd-catalyzed Suzuki cross-coupling of the heteroaryl bromide with a boronate ester derived from <i>N</i>-Boc piperidone, followed by subsequent tetrahydropyridine reduction. Using this method, α-heteroaryl piperidine products featuring a broad range of pharmaceutically relevant azine and diazine substitutions have been prepared

C2-Selective Branched Alkylation of Benzimidazoles by Rhodium(I)-Catalyzed C–H Activation

Herein, we report a Rh­(I)/bisphosphine/K₃PO₄ catalytic system allowing for the first time the selective branched C–H alkylation of benzimidazoles with Michael acceptors. Branched alkylation with <i>N</i>,<i>N</i>-dimethyl acrylamide was successfully applied to the alkylation of a broad range of benzimidazoles incorporating a variety of <i>N</i>-substituents and with both electron-rich and -poor functionality displayed at different sites of the arene. Moreover, the introduction of a quaternary carbon was achieved by alkylation with ethyl methacrylate. The method was also shown to be applicable to the C2-selective branched alkylation of azabenzimidazoles

Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents

The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (<b>1</b>) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of <b>7l</b> and <b>7n</b> with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, <b>7l</b> demonstrated an improved safety profile vs lead <b>7f</b>. We hypothesize that the improved safety profile is related to diminished binding of <b>7l</b> to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of <b>7l</b> stalling of off-target proteins

Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents

The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (<b>1</b>) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of <b>7l</b> and <b>7n</b> with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, <b>7l</b> demonstrated an improved safety profile vs lead <b>7f</b>. We hypothesize that the improved safety profile is related to diminished binding of <b>7l</b> to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of <b>7l</b> stalling of off-target proteins

Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents

The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (<b>1</b>) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of <b>7l</b> and <b>7n</b> with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, <b>7l</b> demonstrated an improved safety profile vs lead <b>7f</b>. We hypothesize that the improved safety profile is related to diminished binding of <b>7l</b> to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of <b>7l</b> stalling of off-target proteins

Germ cell apoptosis induced by artificial cryptorchidism.

Abstrakt. Studovali jsme vliv experimentalniho unilateralniho kryptorchismu na morfologicke a histologicke ukazatele ve tkanich varlat a nadvarlat skupiny samců potkana Wistar. Doba trvani experimentu byla 7 dnů, přičemž byla do kryptorchickych varlat injikovana latka MDOCTM. Pro histologicke hodnoceni kratšich časovych intervalů jsme použili take material z jinych srovnatelnych pokusů, ale bez MDOCTM. Delka a hmotnost kryptorchickych varlat byly vyznamně sniženy v porovnani s kontrolami (22,4% a 52,6%). Degenerativni změny byly patrne již v intervalu jedne hodiny (desintegrace zarodečneho epitelu). Nezrale zarodečne buňky včetně apoptotickych jsme nalezli v lumen kanalku nadvarlete. 6. den jsme v zarodečnem epitelu objevili take mnohojaderne buňky a jeho vakuolizaci. Po sedmi dnech s aplikaci MDOCTM jsme našli vyznamnou degeneraci zarodečneho epitelu zahrnujici mnoho znaků od vakuolizace epitelu po značne množstvi apoptotickych buněk. Take jsme nalezli velke množstvi infiltrovanych makrofagů. Nezazmamenali jsme žadne degenerativni znaky u kontralateralnich kontrol, ani u kontroly, kde jsme opět vratili varle do skrota (shame operated).Abstract. We had studied morfological and histological changes of Wistar rat germinal epithelium after experimentally induced cryptorchidism. Our experiment had lasted seven days. Cryptorchic testes was injected by solution of MDOCTM. We used also tissues which was taken from other comparable studies but without MDOCTM for histological evaluation of shorter time intervals. Both size and weight was significantly reduced in cryptorchid testes compared to contralateral and control testes (22.4% and 52.6% respectively). We recorded degenerative changes of germinal epithelium including epithelial desintegration and release of immature and apoptotic cells, which was found in epydidimal tubules, even in one hour interval. Six days after operation, multinucleated cells and vacuolization of epithlelium also appeared. Seven days after operation (and aplication MDOCTM) we found a significant degeneration of germinal epithelium comprising features from vacuoles to apoptotic cells. A large number of macrophages also appeared in this interval. We didn't record any degenerative features in contralateral and control testes.Katedra biologických a lékařských vědDepartment of Biological and Medical SciencesFaculty of Pharmacy in Hradec KrálovéFarmaceutická fakulta v Hradci Králov