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1.
Bioorg Med Chem Lett ; 92: 129394, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37379958

RESUMO

Our previous work on the optimization of a new class of small molecule PCSK9 mRNA translation inhibitors focused on empirical optimization of the amide tail region of the lead PF-06446846 (1). This work resulted in compound 3 that showed an improved safety profile. We hypothesized that this improvement was related to diminished binding of 3 to non-translating ribosomes and an apparent improvement in transcript selectivity. Herein, we describe our efforts to further optimize this series of inhibitors through modulation of the heterocyclic head group and the amine fragment. Some of the effort was guided by an emerging cryo electron microscopy structure of the binding mode of 1 in the ribosome. These efforts led to the identification of 15 that was deemed suitable for evaluation in a humanized PCSK9 mouse model and a rat toxicology study. Compound 15 demonstrated a dose dependent reduction of plasma PCSK9 levels. The rat toxicological profile was not improved over that of 1, which precluded 15 from further consideration as a clinical candidate.

2.
Bioorg Med Chem Lett ; 29(16): 2025-2033, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307886

RESUMO

Sleep and wake are two fundamental states of human existence. Conditions such as insomnia and hypersomnia can have profound negative effects on human health. Many pharmacological interventions impacting sleep and wake are available or are under development. This brief digest surveys early approaches to sleep modulation and highlights recent developments in sleep modulating agents.


Assuntos
Medicamentos Indutores do Sono/uso terapêutico , Transtornos do Sono-Vigília/tratamento farmacológico , Sono/efeitos dos fármacos , Promotores da Vigília/uso terapêutico , Animais , Humanos , Medicamentos Indutores do Sono/farmacocinética , Promotores da Vigília/farmacocinética
3.
Bioorg Med Chem Lett ; 28(23-24): 3685-3688, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30482620

RESUMO

A series of N-(piperidin-3-yl)-N-(pyridin-2-yl)piperidine/piperazine-1-carboxamides were identified as small molecule PCSK9 mRNA translation inhibitors. Analogues from this new chemical series, such as 4d and 4g, exhibited improved PCSK9 potency, ADME properties, and in vitro safety profiles when compared to earlier lead structures.


Assuntos
Amidas/química , Inibidores de PCSK9 , Piperidinas/química , Inibidores de Proteases/química , Amidas/metabolismo , Amidas/farmacologia , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cristalografia por Raios X , Cães , Humanos , Concentração Inibidora 50 , Células Madin Darby de Rim Canino , Conformação Molecular , Pró-Proteína Convertase 9/metabolismo , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade
4.
Angew Chem Int Ed Engl ; 56(51): 16218-16222, 2017 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-29073340

RESUMO

Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18 F-isotopologue validated our liver-targeting approach.


Assuntos
Fígado/efeitos dos fármacos , Inibidores de PCSK9 , Pró-Proteína Convertase 9/biossíntese , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Dose-Resposta a Droga , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/enzimologia , Fígado/metabolismo , Estrutura Molecular , Pró-Proteína Convertase 9/metabolismo , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
5.
J Med Chem ; 66(5): 3195-3211, 2023 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-36802610

RESUMO

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 Molecular
6.
J Med Chem ; 63(22): 13546-13560, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-32910646

RESUMO

Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.


Assuntos
Descoberta de Drogas/métodos , Inibidores Enzimáticos/química , Frutoquinases/antagonistas & inibidores , Frutoquinases/metabolismo , Frutose/efeitos adversos , Doenças Metabólicas/enzimologia , Animais , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Frutose/administração & dosagem , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Resistência à Insulina/fisiologia , Masculino , Doenças Metabólicas/induzido quimicamente , Doenças Metabólicas/tratamento farmacológico , Estrutura Secundária de Proteína , Ratos , Ratos Wistar
7.
Bioorg Med Chem Lett ; 19(10): 2804-7, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19359168

RESUMO

BODIPY-labeled Soraphen A derivative 4 was synthesized and characterized as an acetyl-CoA carboxylase (ACC) binder. Biophysical measurements indicate that the molecule binds in the biotin carboxylase domain where Soraphen A has been shown to bind. The fluorescent label of the BODIPY can be used to biophysically identify a compound that binds to the Soraphen A site of the biotin carboxylase domain versus the carboxytransferase domain of ACC.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Compostos de Boro/química , Macrolídeos/química , Acetil-CoA Carboxilase/metabolismo , Sítios de Ligação , Compostos de Boro/síntese química , Cristalografia por Raios X , Macrolídeos/síntese química , Estrutura Terciária de Proteína
8.
J Am Chem Soc ; 130(48): 16295-309, 2008 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-19006391

RESUMO

The synthesis of the marine neurotoxin azaspiracid-1 has been accomplished. The individual fragments were synthesized by catalytic enantioselective processes: A hetero-Diels-Alder reaction to afford the E- and HI-ring fragments, a carbonyl-ene reaction to furnish the CD-ring fragment, and a Mukaiyama aldol reaction to deliver the FG-ring fragment. The subsequent fragment couplings were accomplished by aldol and sulfone anion methodologies. All ketalization events to form the nonacyclic target were accomplished under equilibrating conditions utilizing the imbedded configurations of the molecule to adopt one favored conformation. A final fragment coupling of the anomeric EFGHI-sulfone anion to the ABCD-aldehyde completed the convergent synthesis of (+)-azaspiracid-1.


Assuntos
Toxinas Marinhas/síntese química , Compostos de Espiro/síntese química , Aldeídos/química , Ânions/química , Carbono/química , Catálise , Quelantes/química , Compostos de Iodo/síntese química , Compostos de Iodo/química , Espectroscopia de Ressonância Magnética , Toxinas Marinhas/química , Metilação , Modelos Moleculares , Estrutura Molecular , Compostos de Espiro/química , Estereoisomerismo , Sulfonas/química , Compostos de Vinila/química
9.
J Med Chem ; 61(23): 10375-10384, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30052440

RESUMO

Lead-like drugs, or drugs below molecular weight 300, are an important and sometimes overlooked component of the current pharmacopeia and contemporary medicinal chemistry practice. To examine the recent state-of-the-art in lead-like drug discovery, we surveyed recent drug approvals from 2011 to 2017 and top 200 prescribed medications, as well as provide case studies on recently approved lead-like drugs. Many of these recent drugs are close analogs of previously known drugs or natural substrates, with a key focus of their medicinal chemistry optimization being the choice of a low molecular weight starting point and maintaining low molecular weight during the optimization. However, the identification of low molecular weight starting points may be limited by the availability of suitable low molecular weight screening sets. To increase the discovery rate of lead-like drugs, we suggest an increased focus on inclusion and prosecution of lead-like starting points in screening libraries.


Assuntos
Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Peso Molecular
10.
J Med Chem ; 60(18): 7835-7849, 2017 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-28853885

RESUMO

Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.


Assuntos
Desenho de Fármacos , Frutoquinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Cristalografia por Raios X , Frutoquinases/química , Frutoquinases/metabolismo , Humanos , Masculino , Simulação de Acoplamento Molecular , Piridinas/química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley
11.
Expert Opin Ther Pat ; 25(10): 1175-90, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26173447

RESUMO

INTRODUCTION: Chronic heart failure (CHF) is the long-term inability of the heart to meet circulatory demands under normal conditions. Effects of CHF can include increased blood volume, increased vascular resistance and compromised contractility leading to fluid retention, dyspnea and fatigue. Current standard of care for chronic systolic heart failure is directed towards managing hypoperfusion through the renin-angiotensin-aldosterone and sympathetic nervous systems. Treatment may also involve reversal of maladaptive cardiac remodeling and prevention of life-threatening arrhythmias. AREAS COVERED: This review highlights small molecule and peptidic agents for the treatment of CHF with patents published between 2011 and 2014. Targets are subdivided into inotropic agents, ventricular remodeling, diuretics and the renin-angiotensin-aldosterone system. EXPERT OPINION: CHF represents a large, unmet medical need where improved therapies are needed. The renin-angiotensin-aldosterone system pathway continues to be a major source of new therapies for CHF with new inotropic therapies emerging. Promising initial clinical results for a few approaches combined with the expectation of additional clinical results in the near future make this an exciting time in the pursuit of new treatments for CHF.


Assuntos
Desenho de Fármacos , Insuficiência Cardíaca/tratamento farmacológico , Peptídeos/farmacologia , Animais , Doença Crônica , Diuréticos/farmacologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Terapia de Alvo Molecular , Patentes como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
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