RESUMO
While intimate feminine hygiene products are widely used as part of daily cleansing routines, little is known about how these products impact the vulvovaginal area and its microbiome stability. This 4 week clinical study assessed tolerance of a novel gel wash containing lactic acid (pH 4.2) for external daily use when used on the external genital area and its effects on skin moisturization, vulvar skin pH, and the vulvar microbiome. After a 7 day pre-study conditioning period, 36 healthy females in three balanced age groups (18-29, 30-44, and 45-55 years) used the gel wash to cleanse their external genital area (mons pubis and vulva) and entire body at least once per day for 28 days. Skin tolerance of the gel wash was assessed by the gynecologist. Effects of the gel wash on vulvar skin microbiota were studied by performing bacterial 16S rRNA and fungal internal transcribed spacer (ITS) microbial richness and diversity analysis. Based on gynecologic assessment after 28 days of use, the gel wash showed acceptable tolerance, with no signs of increased dryness, redness, edema, itching, stinging, or burning. Use of the gel wash was associated with a significant increase in both short-term (single application) and longer-term (daily use for 28 days) skin moisturization. There was no significant change in vulvar skin pH over time with daily product use, and the gel wash did not significantly affect the natural vulvar microbiome species richness or diversity for bacteria or fungi. Results showed that this gel wash is a mild, moisturizing cleanser that maintains the natural pH and microbial diversity of vulvar skin. To our knowledge, this was the first study to assess the effect of an antimicrobial feminine gel wash on the natural pH and vulvar microbiome habitat of the skin using bacterial 16S rRNA and fungal ITS genetic sequencing techniques.
RESUMO
The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.
Assuntos
Benzimidazóis/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacocinética , Desenho de Fármacos , Células HEK293 , Humanos , Estrutura Molecular , Solubilidade , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinéticaRESUMO
The discovery and selection of a highly potent and selective NaV1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein-ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7/química , Piperidinas/química , Piridinas/química , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Animais , Sítios de Ligação , Cães , Meia-Vida , Hepatócitos/metabolismo , Humanos , Infusões Intravenosas , Concentração Inibidora 50 , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Dor/tratamento farmacológico , Dor/patologia , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ligação Proteica , Estrutura Terciária de Proteína , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Tiadiazóis , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêuticoRESUMO
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Éteres Fenílicos/farmacologia , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Linhagem Celular , Citocromo P-450 CYP2C9/metabolismo , Inibidores do Citocromo P-450 CYP2C9/síntese química , Inibidores do Citocromo P-450 CYP2C9/química , Inibidores do Citocromo P-450 CYP2C9/farmacocinética , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Desenho de Fármacos , Humanos , Microssomos Hepáticos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/química , Éteres Fenílicos/síntese química , Éteres Fenílicos/química , Éteres Fenílicos/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinéticaRESUMO
Visceral leishmaniasis is a severe parasitic disease that is one of the most neglected tropical diseases. Treatment options are limited, and there is an urgent need for new therapeutic agents. Following an HTS campaign and hit optimization, a novel series of amino-pyrazole ureas has been identified with potent in vitro antileishmanial activity. Furthermore, compound 26 shows high levels of in vivo efficacy (>90%) against Leishmania infantum, thus demonstrating proof of concept for this series.
Assuntos
Antiparasitários/química , Leishmania donovani/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Pirazóis/química , Ureia/análogos & derivados , Ureia/química , Animais , Antiparasitários/farmacocinética , Antiparasitários/farmacologia , Cricetinae , Feminino , Humanos , Leishmaniose Visceral/tratamento farmacológico , Mesocricetus , Microssomos/metabolismo , Pirazóis/farmacocinética , Pirazóis/farmacologia , Relação Estrutura-Atividade , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.
Assuntos
Azepinas/química , Fármacos do Sistema Nervoso Central/química , Pirimidinas/química , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/química , Animais , Azepinas/síntese química , Azepinas/farmacologia , Barreira Hematoencefálica/metabolismo , Células CHO , Fármacos do Sistema Nervoso Central/síntese química , Fármacos do Sistema Nervoso Central/farmacologia , Cricetulus , Cães , Desenho de Fármacos , Humanos , Células Madin Darby de Rim Canino , Permeabilidade , Pirimidinas/síntese química , Pirimidinas/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Relação Estrutura-Atividade , Incontinência Urinária por Estresse/tratamento farmacológicoRESUMO
The coupling of aromatic moieties with saturated heterocyclic partners is currently an area of significant interest for the pharmaceutical industry. Herein, we present a procedure for the metal-free coupling of 4-, 5-, and 6-membered saturated heterocyclic p-methoxyphenyl (PMP) sulfonylhydrazones with aryl and heteroaromatic boronic acids. This procedure enables a simple, two-step synthesis of a range of functionalized sp(2)-sp(3) linked bicyclic building blocks, including oxetanes, piperidines, and azetidines, from their parent ketones.
Assuntos
Ácidos Borônicos/química , Compostos Heterocíclicos/química , Hidrazonas/química , Metais/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
Anti-nicotine vaccines may aid smoking cessation via the induction of anti-nicotine antibodies (Ab) which reduce nicotine entering the brain, and hence the associated reward. Ab function depends on both the quantity (titer) and the quality (affinity) of the Ab. Anti-nicotine vaccines tested previously in clinical studies had poor efficacy despite high Ab titer, and this may be due to inadequate function if Ab of low affinity were induced. In this study, we designed and synthesized a series of novel nicotine-like haptens which were all linked to diphtheria toxoid (DT) as carrier, but which differed in the site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. The resulting hapten conjugates were evaluated in a mouse model, using CpG (a TLR9 agonist) and aluminum hydroxide (Al(OH)3) as adjuvants, whereby Ab titers, affinity and function were evaluated using a radiolabeled nicotine challenge model. A series of additional linkers varying in length, rigidity and polarity were used with a single hapten to generate additional DT-conjugates, which were also tested in mice. Conjugates made with different haptens resulted in various titers of anti-nicotine Ab. Several haptens gave similarly high Ab titers, but among these, Ab affinity and hence function varied considerably. Linker also influenced Ab titer, affinity and function. These results demonstrate that immune responses induced in mice by nicotine-conjugate antigens are greatly influenced by hapten design including site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. While both Ab titer and affinity contributed to function, affinity was more sensitive to antigen differences.
Assuntos
Anticorpos/imunologia , Antígenos/imunologia , Haptenos/imunologia , Nicotina/imunologia , Prevenção do Hábito de Fumar , Vacinas/imunologia , Adjuvantes Imunológicos/química , Hidróxido de Alumínio/química , Animais , Anticorpos/sangue , Anticorpos/química , Afinidade de Anticorpos , Especificidade de Anticorpos , Antígenos/química , Toxoide Diftérico/química , Toxoide Diftérico/imunologia , Feminino , Haptenos/química , Humanos , Imunoconjugados/química , Camundongos , Camundongos Endogâmicos BALB C , Mimetismo Molecular , Nicotina/química , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/imunologia , Engenharia de Proteínas/métodos , Fumar/imunologia , Relação Estrutura-Atividade , Vacinas/administração & dosagem , Vacinas/químicaRESUMO
Ion channels are membrane proteins expressed in almost all living cells. The sequencing of the human genome has identified more than 400 putative ion channels, but only a fraction of these have been cloned and functionally tested. The widespread tissue distribution of ion channels, coupled with the plethora of physiological consequences of their opening and closing, makes ion-channel-targeted drug discovery highly compelling. However, despite some important drugs in clinical use today, as a class, ion channels remain underexploited in drug discovery and many existing drugs are poorly selective with significant toxicities or suboptimal efficacy. This Perspective seeks to review the ion channel family, its structural and functional features, and the diseases that are known to be modulated by members of the family. In particular, we will explore the structure and properties of known ligands and consider the future prospects for drug discovery in this challenging but high potential area.
Assuntos
Descoberta de Drogas , Canais Iônicos/efeitos dos fármacos , Humanos , Canais Iônicos/química , Modelos Moleculares , FilogeniaRESUMO
Optimisation of the potency of a bicyclic CRF antagonist whilst retaining metabolic stability is described. A core change and incorporation of metabolically stable lipophilic groups resulted in a further potency gain without increasing metabolic liability. Pharmacological investigation of binding kinetics led to the identification of compound 25, a sub-nanomolar CRF-1 antagonist with slow dissociation kinetics and an encouraging pharmacokinetic profile.
Assuntos
Hormônio Liberador da Corticotropina/antagonistas & inibidores , Purinas/química , Purinas/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Descoberta de Drogas , Humanos , Cinética , Microssomos Hepáticos/metabolismo , Ligação Proteica , Purinas/farmacocinética , Purinas/farmacologia , RatosRESUMO
New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
Assuntos
Azepinas/síntese química , Pirimidinas/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Animais , Azepinas/química , Azepinas/farmacologia , Azepinas/uso terapêutico , Modelos Animais de Doenças , Cães , Masculino , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos , Agonistas do Receptor 5-HT2 de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Incontinência Urinária/tratamento farmacológicoRESUMO
A novel series of potent and selective sulfonamide derived ß(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/síntese química , Asma/tratamento farmacológico , Benzenoacetamidas/síntese química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Sulfonamidas/síntese química , Administração por Inalação , Agonistas Adrenérgicos beta/farmacocinética , Agonistas Adrenérgicos beta/farmacologia , Animais , Benzenoacetamidas/farmacocinética , Benzenoacetamidas/farmacologia , Broncoconstrição/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Cristalografia por Raios X , Cães , Feminino , Cobaias , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Fígado/metabolismo , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Ratos , Estereoisomerismo , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Traqueia/efeitos dos fármacos , Traqueia/metabolismo , Traqueia/fisiopatologiaRESUMO
The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.
Assuntos
Disfunção Erétil/tratamento farmacológico , Piperidinas/síntese química , Pirrolidinas/síntese química , Receptor Tipo 4 de Melanocortina/agonistas , Administração Intranasal , Administração Oral , Administração Sublingual , Animais , Disponibilidade Biológica , Ensaios Clínicos Fase I como Assunto , Cristalografia por Raios X , Cães , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacologia , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Balancing potency and metabolic stability in a target which favours lipophilic ligands is a considerable challenge. Here we describe two strategies employed to achieve this balance in a series of pyrazolopyrimidine CRF antagonists: moderation of lipophilicity, and incorporation of a metabolically stable lipophilic group.
Assuntos
Pirimidinas/química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Humanos , Ligantes , Microssomos Hepáticos/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Relação Estrutura-AtividadeRESUMO
This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT(2C) agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compound 11 was active in in vivo models of stress urinary incontinence.
Assuntos
Pirimidinonas/química , Pirimidinonas/uso terapêutico , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/uso terapêutico , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Humanos , Pirimidinonas/farmacologia , Receptor 5-HT2B de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade , Uretra/efeitos dos fármacos , Incontinência Urinária/tratamento farmacológicoRESUMO
New 7-sulfonamido-3-benzazepines 3 are disclosed as 5-HT(2C) receptor agonists. Appropriate substitution of the amino group (R(1)R(2)N-) gave compounds that were potent 5-HT(2C) agonists with minimal activation of the 5-HT(2A) and 5-HT(2B) receptors. Furthermore, representative examples had excellent in vitro ADME properties and good selectivity over ion channel activity.
Assuntos
Benzazepinas/síntese química , Benzazepinas/farmacocinética , Agonistas do Receptor 5-HT2 de Serotonina , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Animais , Benzazepinas/química , Humanos , Camundongos , Receptor 5-HT2C de Serotonina/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Células Swiss 3T3RESUMO
The design and profile of a series of adamantyl-containing long acting beta(2)-adrenoreceptor agonists are described. An optimal pharmacokinetic profile of low oral bioavailability was combined with a strong pharmacology profile when assessed using a guinea pig trachea tissue model. A focus was then placed on developing a robust synthetic route to ensure rapid delivery of material for clinical trials.
Assuntos
Adamantano/análogos & derivados , Adamantano/farmacologia , Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacologia , Adamantano/farmacocinética , Administração por Inalação , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacocinética , Animais , Cobaias , Humanos , Traqueia/efeitos dos fármacosRESUMO
The design and profile of a series of indole containing long acting beta(2)-adrenoceptor agonists is described. Evaluation of these analogues using an in vitro guinea pig trachea tissue model demonstrates that analogues within this series have salmeterol-like duration of action with potential for long duration of action in humans.
Assuntos
Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Asma/tratamento farmacológico , Indóis/química , Indóis/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Agonistas Adrenérgicos beta/farmacocinética , Albuterol/análogos & derivados , Albuterol/química , Albuterol/farmacologia , Animais , Disponibilidade Biológica , Células CHO , Células CACO-2 , Cricetinae , Cricetulus , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Cobaias , Humanos , Indóis/farmacocinética , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Modelos Moleculares , Estrutura Molecular , Ratos , Xinafoato de Salmeterol , Fatores de Tempo , Traqueia/efeitos dos fármacosRESUMO
Dysfunction of female sexual desire, arousal, or orgasm affects approximately 30% of women. Early attempts to treat female sexual dysfunction arose out of programs developed for male erectile dysfunction and have proven largely unsuccessful. A new wave of targets is now being pursued; many of these targets are postulated to modulate central pathways. Classical neurotransmitter systems, such as dopamine and serotonin, as well as the neuropeptide melanocortin, are receiving the most attention. Early clinical data look promising; however, clinical trial methodology in female sexual dysfunction is not well developed and only further testing will determine whether these treatments meet regulatory hurdles and satisfy patient need.
Assuntos
Desenho de Fármacos , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Alprostadil/agonistas , Agonistas de Dopamina/uso terapêutico , Feminino , Humanos , Neprilisina/antagonistas & inibidores , Inibidores da Fosfodiesterase 5 , Receptores de Melanocortina/agonistas , Receptores de Melanocortina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina , Disfunções Sexuais Fisiológicas/epidemiologia , Disfunções Sexuais Psicogênicas/epidemiologia , Peptídeo Intestinal Vasoativo/uso terapêuticoRESUMO
The design and profile of a series of saligenin containing long acting beta(2)-adrenoreceptor agonists is described. Evaluation of these analogues using a guinea-pig tissue model demonstrates that analogues within this series have significantly longer durations of action than salmeterol and have the potential for a once daily profile in human.