RESUMO
Vaccines and first-generation antiviral therapeutics have provided important protection against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PLpro) is one of the two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease have demonstrated clinical efficacy, known PLpro inhibitors have, to date, lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLpro translates to in vivo efficacy in a preclinical setting. Here, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PLpro inhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.
Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Proteases Semelhantes à Papaína de Coronavírus , Modelos Animais de Doenças , SARS-CoV-2 , Animais , Camundongos , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Antivirais/farmacocinética , Antivirais/uso terapêutico , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Humanos , COVID-19/virologia , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/uso terapêutico , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Aprendizado de Máquina , Feminino , Replicação Viral/efeitos dos fármacosRESUMO
Diacylglycerol O-acyltransferase 2 (DGAT2) inhibitors have been shown to lower liver triglyceride content and are being explored clinically as a treatment for non-alcoholic steatohepatitis (NASH). This work details efforts to find an extended-half-life DGAT2 inhibitor. A basic moiety was added to a known inhibitor template, and the basicity and lipophilicity were fine-tuned by the addition of electrophilic fluorines. A weakly basic profile was required to find an appropriate balance of potency, clearance, and permeability. This work culminated in the discovery of PF-07202954 (12), a weakly basic DGAT2 inhibitor that has advanced to clinical studies. This molecule displays a higher volume of distribution and longer half-life in preclinical species, in keeping with its physicochemical profile, and lowers liver triglyceride content in a Western-diet-fed rat model.
RESUMO
Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Recently, there have been several reports that predicted loss of function variants in HSD17B13 protect against the progression of steatosis to non-alcoholic steatohepatitis with fibrosis and hepatocellular carcinoma. Here we report crystal structures of full length HSD17B13 in complex with its NAD+ cofactor, and with lipid/detergent molecules and small molecule inhibitors from two distinct series in the ligand binding pocket. These structures provide insights into a mechanism for lipid droplet-associated proteins anchoring to membranes as well as a basis for HSD17B13 variants disrupting function. Two series of inhibitors interact with the active site residues and the bound cofactor similarly, yet they occupy different paths leading to the active site. These structures provide ideas for structure-based design of inhibitors that may be used in the treatment of liver disease.
Assuntos
17-Hidroxiesteroide Desidrogenases , Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Proteínas Associadas a Gotículas Lipídicas , Lipídeos , 17-Hidroxiesteroide Desidrogenases/químicaRESUMO
The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.
Assuntos
Apetite , Receptor Tipo 4 de Melanocortina , Ratos , Humanos , Animais , Caquexia/tratamento farmacológico , Anorexia/tratamento farmacológico , Conformação MolecularRESUMO
A nickel-catalyzed reductive cross-coupling of alkylpyridinium salts and aryl bromides has been developed using Mn as the reductant. Both primary and secondary alkylpyridinium salts can be used, and high functional group and heterocycle tolerance is observed, including for protic groups. Mechanistic studies indicate the formation of an alkyl radical, and controlling its fate was key to the success of this reaction.
Assuntos
Aminas/química , Bromo , Piridinas/química , Ácidos Borônicos/química , Catálise , Radicais Livres/química , Cloreto de Magnésio , Manganês/química , Níquel/química , Oxirredução , Compostos de Piridínio/químicaRESUMO
A nickel-catalyzed cross-coupling of benzylic pyridinium salts with arylboronic acids was developed. Coupled with chemoselective pyridinium formation, this method allows benzyl primary amines to be efficiently converted to di(hetero)arylmethanes. Excellent heteroaryl and functional group tolerance is observed, and a one-pot procedure enables benzylic amines to be converted to diarylmethanes directly.
Assuntos
Aminas/química , Catálise , Estrutura Molecular , Níquel , Compostos de Piridínio , SaisRESUMO
The development of a convergent fragment coupling strategy for the enantioselective total syntheses of a group of rearranged spongian diterpenoids that harbor the cis-2,8-dioxabicyclo[3.3.0]octan-3-one unit is described. The key bond disconnection relies on a late-stage fragment coupling between a tertiary carbon radical and an electron-deficient alkene to unite two ring systems and form two new stereocenters, one of which is quaternary, in a stereoselective and efficient manner. This strategy is applied toward scalable 14-15 step syntheses of three rearranged spongian diterpenoids, cheloviolenes A and B, and dendrillolide C.
RESUMO
Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M1 PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M1-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M1 is sufficient to elicit cholinergic AEs.
Assuntos
Isoindóis/farmacologia , Lactamas/farmacologia , Oxazóis/farmacologia , Receptor Muscarínico M1/agonistas , Convulsões/induzido quimicamente , Regulação Alostérica , Anfetamina/farmacologia , Animais , Ataxia/induzido quimicamente , Diarreia/induzido quimicamente , Cães , Donepezila , Desenho de Fármacos , Feminino , Humanos , Indanos/farmacologia , Isoindóis/administração & dosagem , Isoindóis/síntese química , Isoindóis/toxicidade , Lactamas/administração & dosagem , Lactamas/síntese química , Lactamas/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Oxazóis/administração & dosagem , Oxazóis/síntese química , Oxazóis/toxicidade , Piperidinas/farmacologia , Ratos Wistar , Receptor Muscarínico M1/antagonistas & inibidores , Escopolamina/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Tiadiazóis/farmacologia , Vômito/induzido quimicamenteRESUMO
It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.
Assuntos
Descoberta de Drogas , Ácidos Picolínicos/farmacologia , Receptor Muscarínico M1/agonistas , Tiazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Ratos , Receptor Muscarínico M1/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
Selective activation of the M1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Amidas/química , Amidas/farmacologia , Indóis/química , Indóis/farmacologia , Receptor Muscarínico M1/metabolismo , Amidas/farmacocinética , Animais , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Indóis/farmacocinética , Camundongos , Simulação de Acoplamento Molecular , Receptor Muscarínico M1/agonistasRESUMO
The total asymmetric synthesis of (+)- and (-)-clusianone and (+)- and (-)-clusianone methyl enol ether is reported. Asymmetric induction is achieved through the use of ACC alkylation, providing the key intermediates with an er of 99:1. The four synthetic compounds were evaluated for their anti-HIV activity. Both (+)- and (-)-clusianone displayed significant anti-HIV activity.
Assuntos
Fármacos Anti-HIV/síntese química , Compostos Bicíclicos com Pontes/química , Éteres/química , HIV/efeitos dos fármacos , Alquilação , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Benzofenonas , Benzoquinonas , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Humanos , EstereoisomerismoRESUMO
A broadly applicable asymmetric synthetic strategy utilizing N-amino cyclic carbamate alkylation that provides access to the various stereochemical permutations of a common structural motif found in many polycyclic polyprenylated acylphloroglucinols is described. The utility of this methodology is demonstrated through the first asymmetric total synthesis of the antiviral agent (+)-clusianone.
Assuntos
Antivirais/síntese química , Compostos Bicíclicos com Pontes/síntese química , Alquilação , Antivirais/química , Antivirais/farmacologia , Benzofenonas , Benzoquinonas , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Carbamatos , Hidrazonas/química , Estrutura Molecular , Floroglucinol/química , EstereoisomerismoRESUMO
The direct addition of enolizable aldehydes and α-halo thioesters to produce ß-hydroxy thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high syn-selectivity, which is the opposite of that produced for (thio)esters under conventional conditions. Moreover, excellent diastereoselectivity results when a chiral nonracemic α-hydroxy aldehyde derivative is used.
Assuntos
Aldeídos/química , Carbono/química , Ésteres/química , Cinética , OxirreduçãoRESUMO
An asymmetric Mannich reaction of phenylacetate thioesters and sulfonylimines using cinchona alkaloid-based amino (thio)urea catalysts is reported that employs proximity-assisted soft enolization. This approach to enolization is based on the cooperative action of a carbonyl-activating hydrogen bonding (thio)urea moiety and an amine base contained within a single catalytic entity to facilitate intracomplex deprotonation. Significantly, this allows thioesters over a range of acidity to react efficiently, thereby opening the door to the development of a general mode of enolization-based organocatalysis of monocarboxylic acid derivatives.
Assuntos
Carbono/química , Alcaloides de Cinchona/química , Fenilacetatos/química , Compostos de Enxofre/química , Aminas/química , Catálise , Técnicas de Química Combinatória , Ésteres , Estrutura MolecularRESUMO
The Manalpha1,3(Xylbeta1,2)Manalpha structural motif is common to both capsular polysaccharides of Cryptococcus neoformans and to cryptococcal glycosphingolipids. Comparative analysis of glycosphingolipid structural profiles in wild-type and mutant strains showed that the Xylbeta1,2-transferase (Cxt1p) that participates in capsular polysaccharide biosynthesis is also the sole transferase responsible for adding xylose to C. neoformans glycosphingolipids.