RESUMEN
Research collaborations and licensing deals are critical for the discovery and development of life-saving drugs. This practice has been ongoing since the inception of the pharmaceutical industry. The current process of drug discovery and development is complex, regulated, and highly regimented, having evolved over time. Academia excels in the discovery of fundamental scientific concepts and biological processes, while industry excels in translational science and product development. Potential for collaboration exists at every step of the drug discovery and development continuum. This perspective walks through such collaborative activities, provides examples, and offers tips for potential collaborations.
Asunto(s)
Descubrimiento de Drogas , Industria Farmacéutica , Humanos , Historia del Siglo XX , Conducta Cooperativa , Historia del Siglo XXI , Desarrollo de Medicamentos , AcademiaRESUMEN
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Iminas/farmacología , Pirimidinonas/farmacología , Renina/antagonistas & inhibidores , Administración Oral , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Iminas/síntesis química , Iminas/química , Modelos Moleculares , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
The synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Aß40 levels upon subcutaneous and oral administration to rats.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Ácido Aspártico Endopeptidasas/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Diseño de Fármacos , Descubrimiento de Drogas , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
A scaffold hopping strategy was successfully applied in discovering 2-aminooxazole amides as potent DGAT1 inhibitors for the treatment of dyslipidemia. Further optimization in potency and PK properties resulted in a lead series with oral in vivo efficacy in a mouse postprandial triglyceridemia (PPTG) assay.
Asunto(s)
Amidas/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Oxazoles/farmacología , Triglicéridos/sangre , Animales , Humanos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Peptide nucleic acids (PNAs) are antisense molecules with excellent polynucleotide hybridization properties; they are resistant to nuclease degradation but often have poor cell permeability leading to moderate cellular activity and limited clinical results. The addition of cationic substitutions (positive charges) to PNA molecules greatly increases cell permeability. In this report, we describe the synthesis and polynucleotide hybridization properties of a novel cationic/amino-alkyl nucleotide base-modified PNA (OPNA). This study was designed to quantitate the effect the cationic/amino-alkyl nucleotide base modification had on the kinetic and thermodynamic properties of OPNA-DNA hybridization using surface plasmon resonance and UV thermal melt studies. Kinetic studies reveal a favorable 10-30 fold increase in affinity for a single cationic modification on the base of an adenine, cytosine, or guanidine OPNA sequence compared to the nonmodified PNA strand. The increase in affinity is correlated directly with a favorable decrease in the dissociation rate constant and increase in the association rate constant. Introducing additional amino-alkyl base modifications further favors a decrease in the dissociation rate (3-10-fold per amino-alkyl). The thermodynamics driving the OPNA hybridization is promoted by an additional favorable -80 kJ/mol enthalpy of binding for a single amino-alkyl modification compared to the PNA strand. This increase in enthalpy is consistent with an ion-ion interaction with the DNA strand. These kinetic and thermodynamic hybridization studies reveal for the first time that this type of cationic/amino-alkyl base-modified PNA has favorable hybridization properties suitable for development as an antisense oligomer.
RESUMEN
Based on in house screening lead compound 1 for the NAR project, SAR studies have been focused on the modification of the C2 ethers of the pyrimidinedione core structure. In this effort, an unpredictable SAR trend was overcome in the alkyl ether and arylalkyl ether series to identify compound 24 with improved in vitro activity compared to nicotinic acid. More consistent and predictable SAR was achieved in the propargyl ether series. Lead compound 41 was identified with good in vitro and in vivo activity in rat, and much improved rat PK profile.
Asunto(s)
Éteres/farmacología , Lactonas/farmacología , Pirimidinas/farmacología , Receptores Nicotínicos/metabolismo , Éteres/síntesis química , Éteres/química , Humanos , Lactonas/síntesis química , Lactonas/química , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a â¼6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Pirazolonas/farmacología , Quinolinas/farmacología , Esquizofrenia/tratamiento farmacológico , Administración Oral , Animales , Cristalografía por Rayos X , Maleato de Dizocilpina/antagonistas & inhibidores , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Ensayos Analíticos de Alto Rendimiento , Humanos , Modelos Moleculares , Estructura Molecular , Pirazolonas/administración & dosificación , Pirazolonas/química , Quinolinas/administración & dosificación , Quinolinas/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aß following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/antagonistas & inhibidores , Anticonvulsivantes/síntesis química , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Hidantoínas/síntesis química , Administración Oral , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Animales , Anticonvulsivantes/farmacología , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Hidantoínas/farmacología , Modelos Moleculares , Unión Proteica , Ratas , Ratas Sprague-DawleyRESUMEN
SAR exploration at C-6 and C-8 positions of the tricyclic sulfone series was carried out. Several functional groups were found to be well tolerated at C-6 and C-8 positions. Selective combination of C-6 and C-8 modification resulted in new tricyclic sulfone analogs with efficacy in in vivo mouse Aß(40) lowering model.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Sulfonas/síntesis química , Sulfonas/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Ciclización , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Fragmentos de Péptidos/metabolismo , Relación Estructura-Actividad , Sulfonas/químicaRESUMEN
A series of 2-piperidinopiperidine-5-arylthiadiazoles was synthesized and subjected to a structure-activity relationship (SAR) investigation. The potency of this series was improved to the single digit nanomolar range. The key analogs were shown to be free of P450 issues, and they also maintained good ex vivo activity and brain penetration.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/metabolismo , Tiadiazoles/química , Tiadiazoles/farmacología , Animales , Encéfalo/metabolismo , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Ratones , Ratas , Relación Estructura-Actividad , Tiadiazoles/farmacocinéticaRESUMEN
The synthesis of a novel series of iminoheterocycles and their structure-activity relationship (SAR) as modulators of gamma-secretase activity will be detailed. Encouraging SAR generated from a monocyclic core led to a structurally unique bicyclic core. Selected compounds exhibit good potency as gamma-secretase modulators, excellent rat pharmacokinetics, and lowering of Abeta42 levels in various in vivo models.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Iminas/química , Iminas/uso terapéutico , Fragmentos de Péptidos/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Encéfalo/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Humanos , Iminas/farmacocinética , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/antagonistas & inhibidores , Ratas , Relación Estructura-ActividadRESUMEN
A series of novel dopamine D(1) antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D(1) activity and more than 1000-fold selectivity over D(2). We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D(1) antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.
Asunto(s)
Benzazepinas/química , Benzazepinas/farmacología , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D1/antagonistas & inhibidores , Animales , Ratas , Receptores de Dopamina D1/fisiologíaRESUMEN
A series of spiro-azetidines and azetidinones has been evaluated as novel blockers of the T-type calcium channel (Ca(V)3.2) which is a new therapeutic target for the potential treatment of both inflammatory and neuropathic pain. Confirmation and optimization of the potency, selectivity and DMPK properties of leads will be described.
Asunto(s)
Azetidinas/química , Bloqueadores de los Canales de Calcio/síntesis química , Canales de Calcio Tipo T/química , Piperidinas/química , Compuestos de Espiro/química , Animales , Azetidinas/síntesis química , Azetidinas/uso terapéutico , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo T/metabolismo , Diseño de Fármacos , Humanos , Dolor/tratamiento farmacológico , Unión Proteica , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Receptores Notch/efectos de los fármacos , Sulfonas/química , Sulfonas/farmacología , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Ratones , Modelos Moleculares , Sulfonas/síntesis químicaRESUMEN
The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Inhibidores de Proteasas/química , Tartratos/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animales , Sitios de Unión , Simulación por Computador , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Ratas , Relación Estructura-Actividad , Tartratos/síntesis química , Tartratos/farmacocinéticaRESUMEN
A novel series of TNF-alpha convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Proteínas ADAM/metabolismo , Descubrimiento de Drogas , Inhibidores de Proteasas/química , Tartratos/química , Factor de Necrosis Tumoral alfa/metabolismo , Proteína ADAM17 , Sitios de Unión , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Humanos , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacología , Tartratos/metabolismo , Tartratos/farmacologíaRESUMEN
Herein, we disclose three structurally differentiated γ-secretase modulators (GSMs) based on an oxadiazine scaffold. The analogues from series I potently inhibit the generation of Aß42 in vitro when the substituents at 3 and 4 positions of the oxadiazine moiety adopt an α orientation (cf. 11). To address the concern around potential reactivity of the exocyclic double bond present in series I toward nucleophilic attack, compounds containing either an endocyclic double bond, such as 20 (series II), or devoid of an olefinic moiety, such as 27 (series III), were designed and validated as novel GSMs. Compound 11 and azepine 20 exhibit robust lowering of CSF Aß42 in rats treated with a 30 mg/kg oral dose.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Alquenos/química , Alquenos/farmacología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/líquido cefalorraquídeo , Animales , Sitios de Unión/fisiología , Células HEK293 , Humanos , Oxadiazoles/química , Oxadiazoles/farmacología , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/líquido cefalorraquídeo , Ratas , Relación Estructura-ActividadRESUMEN
A series of novel 1,3-benzodiazapine based D1 antagonists was designed according to the understanding of pharmacophore models derived from SCH 23390 (1b), a potent and selective D1 antagonist. The new design features an achiral cyclic-amidine that maintains desired basicity. Solid phase synthesis was developed for SAR development of the novel dopamine antagonists.
Asunto(s)
Benzodiazepinas/química , Antagonistas de Dopamina/química , Neurotransmisores/química , Receptores de Dopamina D1/antagonistas & inhibidores , Benzazepinas/química , Benzazepinas/farmacología , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacología , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Diseño de Fármacos , Humanos , Neurotransmisores/síntesis química , Neurotransmisores/farmacología , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Relación Estructura-ActividadRESUMEN
A class of novel 2-aminobenzothiazoles have been identified as NPY Y(1) antagonists. Various N-heterocyclic substituted aminophenethyl-2-aminobenzothiazole analogs were synthesized to explore the SAR. Isothiourea analogs and ligands with high potency (K(i) 30 nM) have been identified.
Asunto(s)
Descubrimiento de Drogas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Tiourea/farmacología , Ciclización , Relación Dosis-Respuesta a Droga , Ligandos , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Tiourea/análogos & derivados , Tiourea/químicaRESUMEN
A series of spiro-piperidine azetidinone were synthesized and evaluated as potential TRPV1 antagonists. An important issue of plasma stability was investigated and resolved. Further focused SAR study lead to the discovery of a potent antagonist with good oral pharmacokinetic profile in rat.