RESUMO
Acromegaly is a chronic systemic disease characterized by facial and peripheral changes caused by soft tissue overgrowth and is associated with multiple comorbidities. Despite available surgical and medical therapies, suitable treatments for acromegaly are still lacking. Efficient drug development requires an understanding of the exposure-response (E-R) relationship based on nonclinical and early clinical studies. We aimed to establish a platform to facilitate the development of novel drugs to treat acromegaly. We evaluated the E-R relationship of the growth hormone (GH)-inhibitory effect of the somatostatin analog octreotide under growth hormone-releasing hormone + arginine stimulation in healthy participants and compared the results with historical data for patients with acromegaly. This randomized five-way crossover study included two placebo and three active-treatment periods with different doses of octreotide acetate. GH secretion in the two placebo periods was comparable, which confirmed the reproducibility of the response with no carryover effect. GH secretion was inhibited by low-, medium-, and high-dose octreotide acetate in a dose-dependent manner. We also examined the E-R relationship in monkeys as a preclinical drug evaluation study and in rats as a more convenient and simple system for screening candidate drugs. The E-R relationships and EC50 values were similar among animals, healthy participants, and patients with acromegaly, which suggests that GH stimulation studies in early research and development allowed simulation of the drug response in patients with acromegaly. SIGNIFICANCE STATEMENT: This study demonstrated similar exposure-response relationships in terms of the growth hormone-inhibitory effect of octreotide after growth hormone-releasing hormone stimulation among healthy participants, monkeys, and rats. The research methods and analyses utilized in this study will be useful for simulating the dosages and therapeutic effects of drugs for acromegaly and will facilitate the research and development of novel therapeutic agents with similar modes of action.
Assuntos
Acromegalia/sangue , Acromegalia/tratamento farmacológico , Hormônio Liberador de Hormônio do Crescimento/antagonistas & inibidores , Hormônio Liberador de Hormônio do Crescimento/sangue , Octreotida/uso terapêutico , Pesquisa Translacional Biomédica/métodos , Adolescente , Adulto , Animais , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Previsões , Humanos , Macaca fascicularis , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/sangue , Resultado do Tratamento , Adulto JovemRESUMO
Analogs 8-aza-16-aryl prostaglandin E(1) (PGE(1)) and 8-aza-5-thia-16-arylPGE(1) were synthesized and evaluated with respect to their subtype receptor affinity and EP4 agonist activity for the purposes of identifying subtype-selective EP4 agonists that demonstrate oral efficacy. Using an inhibition assay of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in rats, representative compounds were evaluated for their pharmacokinetic profiles and in vivo efficacy. Structure-activity relationships (SARs) were characterized and presented. Of the compounds tested, several demonstrated better oral exposure and/or in vivo efficacy compared with the previously reported analog 2a.
Assuntos
Alprostadil/análogos & derivados , Prostaglandinas E Sintéticas/química , Prostaglandinas E Sintéticas/farmacologia , Receptores de Prostaglandina E Subtipo EP4/agonistas , Administração Oral , Alprostadil/administração & dosagem , Alprostadil/síntese química , Alprostadil/química , Alprostadil/farmacocinética , Alprostadil/farmacologia , Animais , Humanos , Lipopolissacarídeos/imunologia , Prostaglandinas E Sintéticas/administração & dosagem , Prostaglandinas E Sintéticas/síntese química , Prostaglandinas E Sintéticas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP4/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Acromegaly is a disease caused by the oversecretion of growth hormone. It is currently treated by intravenous injection with cyclic peptide drugs that activate somatostatin receptor subtype 2 (SSTR2). Here, novel nonpeptidic, small-molecule, and orally active SSTR2 agonists were identified from a hit compound (13). Pharmacophore studies enabled scaffold hopping to obtain a unique 3,4,5-trisubstituted pyridine motif. Further optimization conferred potent SSTR2 agonistic activity and metabolic stability. Several compounds were evaluated and these showed good oral pharmacokinetic profiles in rats, and one representative compound (25) showed highly potent inhibition of growth hormone secretion induced by growth hormone-releasing hormone in rats. Based on these results, 25 was identified as a promising lead for further optimization. A structure-activity relationship (SAR) study and the metabolic stability data for this compound are also described.