RESUMEN
Quantum mechanical calculations have been used to study the intramolecular additions of hydroxylamines to alkenes and alkynes ("reverse Cope eliminations"). In intermolecular reverse Cope eliminations, alkynes are more reactive than alkenes. However, competition experiments have shown that tethering the hydroxylamine to the alkene or alkyne can reverse the reactivity order from that normally observed. The exact outcome depends on the length of the tether. In agreement with experiment, a range of density functional theory methods and CBS-QB3 calculations predict that the activation energies for intramolecular reverse Cope eliminations follow the order 6-exo-dig < 5-exo-trig < 5-exo-dig ≈ 7-exo-dig. The order of the barriers for the 5-, 6-, and 7-exo-dig reactions of alkynes arises mainly from differences in tether strain in the transition states (TSs), but is also influenced by the TS interaction between the hydroxylamine and alkyne. Cyclization onto an alkene in the 5-exo-trig fashion incurs slightly less tether strain than a 6-exo-dig alkyne cyclization, but its activation energy is higher because the hydroxylamine fragment must distort more before the TS is reached. If the alkene terminus is substituted with two methyl groups, the barrier becomes so much higher that it is also disfavored compared to the 5- and 7-exo-dig cyclizations.
Asunto(s)
Alquenos/química , Alquinos/química , Hidroxilaminas/química , Teoría Cuántica , Ciclización , Estructura MolecularRESUMEN
A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.
Asunto(s)
Benzoxazoles/farmacocinética , Indoles/farmacocinética , Trastornos de la Memoria/tratamiento farmacológico , Agonistas Muscarínicos/farmacocinética , Nootrópicos/farmacocinética , Receptor Muscarínico M1/metabolismo , Animales , Benzoxazoles/química , Benzoxazoles/uso terapéutico , Encéfalo/metabolismo , Indoles/química , Indoles/uso terapéutico , Agonistas Muscarínicos/química , Agonistas Muscarínicos/uso terapéutico , Nootrópicos/química , Nootrópicos/uso terapéutico , Oxindoles , RatasRESUMEN
Further optimization of the biaryl amide series via extensively exploring structure-activity relationships resulted in potent and subtype selective M(1) agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure-activity relationships, subtype selectivity for M(1) over M(2-5), and DMPK properties of these novel compounds are described.
Asunto(s)
Amidas/síntesis química , Amidas/farmacocinética , Hidrocarburos Aromáticos/síntesis química , Hidrocarburos Aromáticos/farmacocinética , Receptor Muscarínico M1/agonistas , Amidas/farmacología , Animales , Barrera Hematoencefálica/metabolismo , Sistema Nervioso Central/metabolismo , Descubrimiento de Drogas , Hidrocarburos Aromáticos/farmacología , Estructura Molecular , Ratas , Relación Estructura-Actividad , Distribución TisularRESUMEN
Biaryl amides were discovered as novel and subtype selective M(1) muscarinic acetylcholine receptor agonists. The identification, synthesis, and initial structure-activity relationships that led to compounds 3j and 4c, possessing good M(1) agonist potency and intrinsic activity, and subtype selectivity for M(1) over M(2-5), are described.
Asunto(s)
Amidas/síntesis química , Hidrocarburos Aromáticos/síntesis química , Receptor Muscarínico M1/agonistas , Amidas/farmacología , Descubrimiento de Drogas , Hidrocarburos Aromáticos/farmacología , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Virtual screening of the corporate compound collection yielded compound 1 as a subtype selective muscarinic M1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M1 receptor agonists 4 and 5 with excellent potency, general and subtype selectivity, and pharmacokinetic (PK) properties including good central nervous system (CNS) penetration and oral bioavailability. Compound 5 showed robust in vivo activities in animal models of cognition enhancement. The combination of high potency, excellent selectivity, and good PK properties makes compounds 4 and 5 valuable tool compounds for investigating and validating potential therapeutic benefits resulting from selective M1 activation.
RESUMEN
A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.
Asunto(s)
Antipsicóticos/síntesis química , Antipsicóticos/farmacología , Alquilación , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Diseño de Fármacos , Humanos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores de Serotonina/efectos de los fármacos , Proteínas Recombinantes/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacologíaRESUMEN
Aripiprazole is a novel antipsychotic drug, which displays partial agonist activity at the dopamine D(2) receptor. Aripiprazole has been extensively studied pre-clinically, both in vitro and in vivo, and these results have been correlated with clinical findings. However, aripiprazole is metabolised differently in rats and man and these metabolites may contribute to the profile of aripiprazole observed in vivo. We have therefore studied the interaction of aripiprazole and its principal rat and human metabolites in both in vitro models of dopamine hD(2) receptor function and affinity, and of in vivo models of dopamine rat D(2) receptor function. The human metabolite displayed similar levels of partial agonist activity to aripiprazole at the dopamine hD(2) receptor and displayed similar behavioural profile to aripiprazole in vivo, suggesting that in man the metabolite may maintain the effects of aripiprazole. In contrast, the rat metabolite displayed antagonist activity both in vitro and in vivo. Thus care must be taken in ascribing effects seen in vivo with aripiprazole in rats to dopamine D(2) receptor partial agonist activity in man, and that care must also be taken in extrapolating effects seen in rats to man, particularly from long-term studies.
Asunto(s)
Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Antagonistas de los Receptores de Dopamina D2 , Piperazinas/farmacología , Quinolonas/farmacología , Receptores de Dopamina D2/agonistas , Anfetamina , Animales , Antipsicóticos/metabolismo , Antipsicóticos/toxicidad , Aripiprazol , Unión Competitiva , Biotransformación , Células CHO , Catalepsia/inducido químicamente , Cricetinae , Cricetulus , Discinesia Inducida por Medicamentos/etiología , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Células HeLa , Humanos , Masculino , Actividad Motora/efectos de los fármacos , Oxidopamina , Piperazinas/metabolismo , Piperazinas/toxicidad , Quinolonas/metabolismo , Quinolonas/toxicidad , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Especificidad de la Especie , TransfecciónRESUMEN
4-n-Butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine hydrogen chloride (AC-42) is a selective agonist of the muscarinic M(1) receptor previously suggested to interact with an "ectopic" site on this receptor. However, the pharmacological properties of this site (i.e., whether it overlaps to any extent with the classic orthosteric site or represents a novel allosteric site) remain undetermined. In the present study, atropine or pirenzepine significantly inhibited the ability of either carbachol or AC-42 to stimulate inositol phosphate accumulation or intracellular calcium mobilization in Chinese hamster ovary (CHO) cells stably expressing the human M(1) receptor. However, the interaction between either of these antagonists and AC-42 was characterized by Schild slopes significantly less than unity. Increasing the concentrations of atropine revealed that the Schild regression was curvilinear, consistent with a negative allosteric interaction. More direct evidence for an allosteric mode of action of AC-42 was obtained in [(3)H]N-methylscopolamine ([(3)H]NMS) binding studies, in that both AC-42 and the prototypical modulator gallamine failed to fully inhibit specific [(3)H]NMS binding in a manner that was quantitatively described by an allosteric model applied to both modulator data sets. Furthermore, AC-42 and gallamine significantly retarded the rate of [(3)H]NMS dissociation from CHO-hM(1) cell membranes, conclusively demonstrating their ability to bind to a topographically distinct site to change M(1) receptor conformation. These data provide the first direct evidence that AC-42 is an allosteric agonist that activates M(1) receptors in the absence of the orthosteric agonist.
Asunto(s)
Agonistas Muscarínicos/farmacología , Piperidinas/farmacología , Receptor Muscarínico M1/efectos de los fármacos , Regulación Alostérica , Animales , Células CHO , Calcio/metabolismo , Cricetinae , Sondas Moleculares , N-Metilescopolamina/metabolismo , Ensayo de Unión Radioligante , Receptor Muscarínico M1/metabolismoRESUMEN
We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, including our own series of indole piperidine compounds. On the basis of these results, a number of site-directed mutations (SDM) were designed that were intended to verify the proposed docking models. From these it was clear that further refinements would be necessary in the model. This was aided by the publication of a crystal structure of bovine rhodopsin, and a new receptor model was built by homology to this structure. This latest model enabled us to define ligand-docking hypotheses that were in complete agreement with the results of the SDM experiments.
Asunto(s)
Receptores de Quimiocina/antagonistas & inhibidores , Receptores de Quimiocina/metabolismo , Sustitución de Aminoácidos , Animales , Sitios de Unión , Unión Competitiva , Células CHO , Bovinos , Línea Celular , Quimiotaxis/efectos de los fármacos , Cricetinae , Humanos , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Cinética , Modelos Moleculares , Monocitos/efectos de los fármacos , Monocitos/fisiología , Mutagénesis Sitio-Dirigida , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacología , Ensayo de Unión Radioligante , Receptores CCR2 , Receptores de Quimiocina/química , Receptores de Quimiocina/genética , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Rodopsina/química , Rodopsina/genética , Homología Estructural de Proteína , TransfecciónRESUMEN
1 (6-((R)-2-[2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl]-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride) (SB-656104-A), a novel 5-hydroxytryptamine (5-HT(7)) receptor antagonist, potently inhibited [(3)H]-SB-269970 binding to the human cloned 5-HT(7(a)) (pK(i) 8.7+/-0.1) and 5-HT(7(b)) (pK(i) 8.5+/-0.2) receptor variants and the rat native receptor (pK(i) 8.8+/-0.2). The compound displayed at least 30-fold selectivity for the human 5-HT(7(a)) receptor versus other human cloned 5-HT receptors apart from the 5-HT(1D) receptor ( approximately 10-fold selective). 2 SB-656104-A antagonised competitively the 5-carboxamidotryptamine (5-CT)-induced accumulation of cyclic AMP in h5-HT(7(a))/HEK293 cells with a pA(2) of 8.5. 3 Following a constant rate iv infusion to steady state in rats, SB-656104 had a blood clearance (CL(b)) of 58+/-6 ml min(-1) kg(-1) and was CNS penetrant with a steady-state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg(-1)), the compound displayed a t(1/2) of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 micro M, respectively. 4 SB-656104-A produced a significant reversal of the 5-CT-induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5-HT(7) receptor interaction in vivo (ED(50) 2 mg kg(-1)). 5 SB-656104-A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg(-1) i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg(-1) i.p. with no significant effect on the latency to, or amount of, non-REM sleep. SB-269970-A produced qualitatively similar effects in the same study. 6 In summary, SB-656104-A is a novel 5-HT(7) receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5-HT(7) receptors in the modulation of REM sleep.
Asunto(s)
Fenoles/farmacocinética , Pirrolidinas/farmacocinética , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacocinética , Serotonina/análogos & derivados , Sueño REM/efectos de los fármacos , Sueño REM/fisiología , Animales , Células CHO , Línea Celular , Membrana Celular/fisiología , Cricetinae , AMP Cíclico/metabolismo , Vías de Administración de Medicamentos , Regulación de la Expresión Génica , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobayas , Humanos , Hipotermia/inducido químicamente , Fenoles/administración & dosificación , Pirrolidinas/administración & dosificación , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/genética , Serotonina/administración & dosificación , Serotonina/farmacocinética , Serotonina/farmacología , Serotonina/fisiología , Antagonistas de la Serotonina/administración & dosificación , TritioRESUMEN
Novel 5-HT(7) receptor antagonists containing the benzocycloheptanone core were identified from high throughput screening. Molecular modelling and SAR studies have converted these intractable hits into a more potent, selective and tractable series, exemplified by compound (25), SB-691673.
Asunto(s)
Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Indicadores y Reactivos , Isoenzimas/efectos de los fármacos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
A focused SAR study around the previously reported selective 5-HT(7) receptor antagonist, SB-269970-A has resulted in the identification of a structurally related analogue having an improved pharmacokinetic profile. Replacement of the phenolic group in SB-269970-A with an indole moiety, and replacement of the piperidinyl 4-methyl group with a heterocyclic ring system proved to be the key changes leading to the identification of SB-656104-A.