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1.
Org Lett ; 26(12): 2420-2424, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38498905

RESUMO

The discussion herein describes a metallaphotoredox reaction that allows for efficient exploration of benzyl structure-activity relationships in medicinal chemistry. The use of HTE (high-throughput experimentation) and ChemBeads allows for rapid reaction optimization. The formation of di(hetero)arylmethanes via cross-electrophile coupling between aryl bromides and benzyl bromides provides access to diverse chemical space. The breadth of the substrate scope will be discussed, along with the utilization of batch photochemistry for the preparation of this di(hetero)arylmethane motif on a larger scale.

2.
J Med Chem ; 67(3): 2049-2065, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38284310

RESUMO

Human genetic evidence shows that PDE3B is associated with metabolic and dyslipidemia phenotypes. A number of PDE3 family selective inhibitors have been approved by the FDA for various indications; however, given the undesirable proarrhythmic effects in the heart, selectivity for PDE3B inhibition over closely related family members (such as PDE3A; 48% identity) is a critical consideration for development of PDE3B therapeutics. Selectivity for PDE3B over PDE3A may be achieved in a variety of ways, including properties intrinsic to the compound or tissue-selective targeting. The high (>95%) active site homology between PDE3A and B represents a massive obstacle for obtaining selectivity at the active site; however, utilization of libraries with high molecular diversity in high throughput screens may uncover selective chemical matter. Herein, we employed a DNA-encoded library screen to identify PDE3B-selective inhibitors and identified potent and selective boronic acid compounds bound at the active site.


Assuntos
DNA , Coração , Humanos , Domínio Catalítico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3
3.
ACS Chem Biol ; 17(6): 1315-1320, 2022 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-35580266

RESUMO

Interleukin-1 receptor-associated kinase 3 (IRAK3) is a pseudokinase mediator in the human inflammatory pathway, and ablation of its function is associated with enhanced antitumor immunity. Traditionally, pseudokinases have eluded "druggability" and have not been considered tractable targets in the pharmaceutical industry. Herein we disclose a CRISPR/Cas9-mediated knockout of IRAK3 in monocyte-derived dendritic cells that results in an increase in IL-12 production upon lipopolysaccharide (LPS) stimulation. Furthermore, we disclose and characterize Degradomer D-1, which displays selective proteasomal degradation of IRAK3 and reproduces the 1L-12p40 increases observed in the CRISPR/Cas9 knockout.


Assuntos
Citocinas , Quinases Associadas a Receptores de Interleucina-1 , Citocinas/metabolismo , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-12/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Monócitos/metabolismo
4.
Surg Innov ; 26(1): 124-128, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30472923

RESUMO

BACKGROUND: Access to basic anesthetic monitoring in the developing world is lacking, which contributes to the 100 times greater anesthesia-related mortality in low- and middle-income countries. We hypothesize that an environmental sensor with a lower sampling rate could provide some clinical utility by providing CO2 levels, respiratory rate, and support in detection of clinical abnormalities. MATERIALS AND METHODS: A bench-top lung simulation was created to replicate CO2 waveforms, and an environmental sensor was compared with industry-available technology. Sensor response time and respiratory rates were compared between devices. Additionally, an in silico model was created to replicate capnography pathology as waveforms would appear using the environmental sensor. RESULTS AND CONCLUSION: Breath simulations using the bench-top lung simulation produced similar results to industry standards with a degree of variability. Respiratory rates did not differ between the environmental sensor and all other devices tested. Finally, pathological waveforms created in silico carried a certain level of detail regarding ventilatory pathology, which could provide some clinical insight to an anesthesiologist. We believe our prototype is the first step toward making low-cost and portable capnography available in the resource-limited setting, and future efforts should focus on bridging the gap to safer anesthesia and surgery globally.


Assuntos
Anestesia/métodos , Capnografia/instrumentação , Dióxido de Carbono/análise , Monitorização Fisiológica/instrumentação , Pobreza , Anestesia/efeitos adversos , Capnografia/métodos , Desenho de Equipamento , Humanos , Monitorização Fisiológica/métodos , Melhoria de Qualidade , Taxa Respiratória , Fatores Socioeconômicos
5.
ACS Med Chem Lett ; 7(9): 862-7, 2016 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-27660692

RESUMO

Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.

6.
J Med Chem ; 57(20): 8496-502, 2014 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-25211597

RESUMO

Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Química Farmacêutica/métodos , Relação Estrutura-Atividade , Antimaláricos/metabolismo , Técnicas de Química Sintética , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Solubilidade
7.
J Org Chem ; 77(17): 7187-211, 2012 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-22853001

RESUMO

The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.


Assuntos
Azetidinas/farmacocinética , Sistema Nervoso Central/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Animais , Azetidinas/sangue , Azetidinas/síntese química , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sistema Nervoso Central/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Camundongos , Estrutura Molecular , Solubilidade , Compostos de Espiro/sangue , Estereoisomerismo
8.
Tetrahedron ; 67(34): 6131-6137, 2011 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-21822337

RESUMO

Orthogonally protected chiral ß-hydroxy-γ-amino acids can be accessed in >100 g quantities from readily available starting materials and reagents in 3-4 steps. These chiral synthons contain two adjacent stereocenters along with suitably protected functional groups (O-TBS, N-Boc) for downstream reactivity. Implementation of two existing aldol technologies allows rapid access to all possible stereoisomers of 1. The guiding principles during reaction optimization were reaction scalability and operational efficiency. Conversion of the amino acids to a variety of chiral building blocks in 1-2 steps demonstrates their synthetic utility.

9.
J Am Chem Soc ; 132(47): 16962-76, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21067169

RESUMO

An aldol-based build/couple/pair (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, a series of asymmetric syn- and anti-aldol reactions were performed to produce four stereoisomers of a Boc-protected γ-amino acid. In addition, both stereoisomers of O-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the couple step, eight stereoisomeric amides were synthesized by coupling the chiral acid and amine building blocks. The amides were subsequently reduced to generate the corresponding secondary amines. In the pair phase, three different reactions were employed to enable intramolecular ring-forming processes: nucleophilic aromatic substitution (S(N)Ar), Huisgen [3+2] cycloaddition, and ring-closing metathesis (RCM). Despite some stereochemical dependencies, the ring-forming reactions were optimized to proceed with good to excellent yields, providing a variety of skeletons ranging in size from 8- to 14-membered rings. Scaffolds resulting from the RCM pairing reaction were diversified on the solid phase to yield a 14 400-membered library of macrolactams. Screening of this library led to the discovery of a novel class of histone deacetylase inhibitors, which display mixed enzyme inhibition, and led to increased levels of acetylation in a primary mouse neuron culture. The development of stereo-structure/activity relationships was made possible by screening all 16 stereoisomers of the macrolactams produced through the aldol-based B/C/P strategy.


Assuntos
Aldeídos/química , Descoberta de Drogas/métodos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores de Histona Desacetilases/química , Compostos Macrocíclicos/química , Camundongos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Especificidade por Substrato
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