RESUMEN
A new method for solid phase parallel synthesis of chemically and conformationally diverse macrocyclic peptidomimetics is reported. A key feature of the method is access to broad chemical and conformational diversity. Synthesis and mechanistic studies on the macrocyclization step are reported.
Asunto(s)
Química Farmacéutica/métodos , Péptidos Cíclicos/química , Técnicas Químicas Combinatorias , Dimerización , Dipéptidos , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Imitación Molecular , Estructura Molecular , Péptidos/química , Plata/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small-molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid functionality where the peptoid group enabled us to explore side-chain diversity well beyond that of natural amino acids. At the same time, theoretical calculations and experimental assays were used to track and reduce the polarity while closely monitoring the physicochemical properties. This strategy led to the discovery of macrocyclic peptide-peptoid hybrids with high CXCR7 binding affinities (Ki < 100 nM) and measurable passive permeability (Papp > 5 × 10-6 cm/s). Moreover, bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration.
Asunto(s)
Péptidos/química , Péptidos/farmacología , Peptoides/química , Peptoides/farmacología , Receptores CXCR/agonistas , Receptores CXCR/metabolismo , Administración Oral , Animales , Disponibilidad Biológica , Perros , Humanos , Compuestos Macrocíclicos/administración & dosificación , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/farmacología , Células de Riñón Canino Madin Darby , Masculino , Simulación del Acoplamiento Molecular , Péptidos/administración & dosificación , Péptidos/farmacocinética , Peptoides/administración & dosificación , Peptoides/farmacocinética , Ratas , Ratas WistarRESUMEN
A novel class of macrocyclic peptidomimetics was identified and optimized as potent antagonists to the human motilin receptor (hMOT-R). Well-defined structure-activity relationships allowed for rapid optimization of potency that eventually led to high affinity antagonists to hMOT-R. Potency and antagonist functional activity were confirmed both in functional and cell-based assays, as well as on isolated rabbit intestinal smooth muscle strips. Rapid access to this novel class of macrocyclic target structures was made possible through two efficient and complementary solid-phase parallel synthetic approaches, both of which are reported herein.
Asunto(s)
Compuestos Macrocíclicos/síntesis química , Oligopéptidos/síntesis química , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Duodeno/efectos de los fármacos , Duodeno/fisiología , Humanos , Técnicas In Vitro , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Imitación Molecular , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Oligopéptidos/química , Oligopéptidos/farmacología , Conejos , Ensayo de Unión Radioligante , Relación Estructura-ActividadRESUMEN
The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.
Asunto(s)
Activadores de Enzimas/farmacología , Fibrosis Pulmonar Idiopática/enzimología , Fibrosis Pulmonar Idiopática/patología , Pulmón/efectos de los fármacos , Pulmón/patología , Sapogeninas/farmacología , Telomerasa/metabolismo , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Animales , Bleomicina/efectos adversos , Senescencia Celular/efectos de los fármacos , Colágeno/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Activadores de Enzimas/administración & dosificación , Fibroblastos/efectos de los fármacos , Humanos , Fibrosis Pulmonar Idiopática/inducido químicamente , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Pulmón/metabolismo , Ratones , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/enzimología , Sapogeninas/administración & dosificaciónRESUMEN
High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as 1 (Ki=86 nM, EC50=134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (Ki=16 nM, EC50=29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' ß-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.