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1.
J Med Chem ; 60(18): 7764-7780, 2017 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-28817277

RESUMO

We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Piridinas/farmacologia , Piridinas/farmacocinética , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Receptor de Glutamato Metabotrópico 5/metabolismo , Animais , Feminino , Células HEK293 , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Masculino , Simulação de Acoplamento Molecular , Piridinas/efeitos adversos , Piridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 25(21): 4941-4944, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25987375

RESUMO

Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.


Assuntos
Descoberta de Drogas , Epilepsia/tratamento farmacológico , Ativação do Canal Iônico/efeitos dos fármacos , Canal de Potássio KCNQ2/metabolismo , Piperidinas/farmacologia , Pirimidinas/farmacologia , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Eletrochoque , Humanos , Canal de Potássio KCNQ2/agonistas , Microssomos/efeitos dos fármacos , Estrutura Molecular , Piperidinas/administração & dosagem , Piperidinas/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Relação Estrutura-Atividade
3.
J Med Chem ; 57(3): 861-77, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24392688

RESUMO

A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine (PF470, 14) as a highly potent, selective, and orally bioavailable mGluR5 NAM. Compound 14 demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study.


Assuntos
Pirazinas/síntese química , Pirazóis/síntese química , Receptor de Glutamato Metabotrópico 5/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Administração Oral , Regulação Alostérica , Animais , Antiparkinsonianos/efeitos adversos , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Cães , Discinesia Induzida por Medicamentos/tratamento farmacológico , Células HEK293 , Humanos , Hipersensibilidade Tardia/induzido quimicamente , Levodopa/efeitos adversos , Macaca fascicularis , Células Madin Darby de Rim Canino , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Pirazinas/farmacologia , Pirazinas/toxicidade , Pirazóis/farmacologia , Pirazóis/toxicidade , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
4.
J Med Chem ; 55(21): 9055-68, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-23025719

RESUMO

Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥ 1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Azetidinas/química , Barreira Hematoencefálica/metabolismo , Pirazóis/química , Pirazóis/síntese química , Pirimidinas/química , Pirimidinas/síntese química , Pirimidinonas/química , 3',5'-AMP Cíclico Fosfodiesterases/química , Administração Oral , Animais , Azetidinas/síntese química , Azetidinas/farmacocinética , Cristalografia por Raios X , GMP Cíclico/líquido cefalorraquidiano , Ciclopentanos/síntese química , Ciclopentanos/química , Ciclopentanos/farmacocinética , Bases de Dados Factuais , Cães , Desenho de Fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
5.
J Med Chem ; 55(21): 9045-54, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-22780914

RESUMO

6-[(3S,4S)-4-Methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943) is a novel PDE9A inhibitor identified using parallel synthetic chemistry and structure-based drug design (SBDD) and has advanced into clinical trials. Selectivity for PDE9A over other PDE family members was achieved by targeting key residue differences between the PDE9A and PDE1C catalytic site. The physicochemical properties of the series were optimized to provide excellent in vitro and in vivo pharmacokinetics properties in multiple species including humans. It has been reported to elevate central cGMP levels in the brain and CSF of rodents. In addition, it exhibits procognitive activity in several rodent models and synaptic stabilization in an amyloid precursor protein (APP) transgenic mouse model. Recent disclosures from clinical trials confirm that it is well tolerated in humans and elevates cGMP in cerebral spinal fluid of healthy volunteers, confirming that it is a quality pharmacological tool for testing clinical hypotheses in disease states associated with impairment of cGMP signaling or cognition.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Encéfalo/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Pirazóis/síntese química , Pirimidinonas/síntese química , Precursor de Proteína beta-Amiloide/genética , Animais , Domínio Catalítico , Cristalografia por Raios X , GMP Cíclico/metabolismo , Cães , Desenho de Fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirimidinonas/farmacocinética , Pirimidinonas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Sinapses/efeitos dos fármacos , Sinapses/fisiologia
6.
ACS Med Chem Lett ; 3(3): 187-92, 2012 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900455

RESUMO

Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and (13)C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.

7.
PLoS One ; 5(8): e12011, 2010 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-20711499

RESUMO

BACKGROUND: Abolishing the inhibitory signal of intracellular cAMP by phosphodiesterases (PDEs) is a prerequisite for effector T (Teff) cell function. While PDE4 plays a prominent role, its control of cAMP levels in Teff cells is not exclusive. T cell activation has been shown to induce PDE8, a PDE isoform with 40- to 100-fold greater affinity for cAMP than PDE4. Thus, we postulated that PDE8 is an important regulator of Teff cell functions. METHODOLOGY/PRINCIPAL FINDINGS: We found that Teff cells express PDE8 in vivo. Inhibition of PDE8 by the PDE inhibitor dipyridamole (DP) activates cAMP signaling and suppresses two major integrins involved in Teff cell adhesion. Accordingly, DP as well as the novel PDE8-selective inhibitor PF-4957325-00 suppress firm attachment of Teff cells to endothelial cells. Analysis of downstream signaling shows that DP suppresses proliferation and cytokine expression of Teff cells from Crem-/- mice lacking the inducible cAMP early repressor (ICER). Importantly, endothelial cells also express PDE8. DP treatment decreases vascular adhesion molecule and chemokine expression, while upregulating the tight junction molecule claudin-5. In vivo, DP reduces CXCL12 gene expression as determined by in situ probing of the mouse microvasculature by cell-selective laser-capture microdissection. CONCLUSION/SIGNIFICANCE: Collectively, our data identify PDE8 as a novel target for suppression of Teff cell functions, including adhesion to endothelial cells.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Linfócitos T/citologia , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , 3',5'-AMP Cíclico Fosfodiesterases/genética , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL12/genética , Claudina-5 , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Citocinas/metabolismo , Dipiridamol/farmacologia , Endotélio Vascular/citologia , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hidrólise , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Inibidores de Fosfodiesterase/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Fatores de Tempo
8.
J Org Chem ; 64(22): 8267-8274, 1999 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-11674747

RESUMO

A synthetic approach was developed to the C1-C28 subunit of spongistatin 1 (altohyrtin A, 65). The key step was the coupling of the AB and CD spiroketal moieties via an anti-aldol reaction of aldehyde 62 and ethyl ketone 57. The development of a method for the construction of the AB spiroketal fragment is described and included the desymmetrization of C(2)-symmetric diketone 10 and the differentiation of the two primary alcohols of 16. Further elaboration of this advanced intermediate to the desired aldehyde 62 included an Evans' syn-aldol reaction and Tebbe olefination. The synthesis of the CD spiroketal fragment 56 involved the ketalization of a triol-dione, generated in situ by deprotection of 45, to provide a favorable ratio (6-7:1) of spiroketal isomers 46 and 47, respectively. The overall protecting group strategy, involving many selective manipulations of silyl protecting groups, was successfully developed to provide the desired C1-C28 subunit of spongistatin 1 (altohyrtin A) (65).

9.
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