RESUMEN
Herein we describe the continued optimization of M4 positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c]pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology.
Asunto(s)
Amidas/química , Azetidinas/química , Receptor Muscarínico M4/metabolismo , Regulación Alostérica , Amidas/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Unión Proteica , Piridazinas/síntesis química , Piridazinas/química , Piridazinas/metabolismo , Receptor Muscarínico M4/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Subtle modifications were incorporated into the structure of clinical candidate 1. These changes were designed to maintain potency and selectivity while inducing changes in physical properties leading to improved pharmacokinetics in three species. This approach led to the identification of 4 as a potent, selective alphaVbeta3 receptor antagonist that was selected for clinical development based on an improved PK profile and efficacy demonstrated in an in vivo model of bone turnover.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Naftiridinas/química , Animales , Perros , Evaluación Preclínica de Medicamentos/métodos , Humanos , Integrina alfaVbeta3/metabolismo , Macaca mulatta , Masculino , Naftiridinas/metabolismo , Naftiridinas/farmacología , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , RatasRESUMEN
3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.
Asunto(s)
Integrinas/antagonistas & inhibidores , Naftiridinas/farmacología , Osteoporosis/tratamiento farmacológico , Receptores de Vitronectina/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Densidad Ósea/efectos de los fármacos , Resorción Ósea/tratamiento farmacológico , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Concentración 50 Inhibidora , Integrinas/metabolismo , Macaca mulatta , Modelos Moleculares , Naftiridinas/química , Naftiridinas/farmacocinética , Osteoporosis/prevención & control , Ovariectomía , Ratas , Ratas Sprague-Dawley , Receptores de Vitronectina/metabolismo , Relación Estructura-ActividadRESUMEN
A series of novel, highly potent alpha(v)beta(3) receptor antagonists with favorable pharmacokinetic profiles has been identified. In this series of antagonists, 2-aryl beta-amino acids function as potent aspartic acid replacements.
Asunto(s)
Aminoácidos/química , Ésteres/química , Receptores de Vitronectina/antagonistas & inhibidores , Aminoácidos/síntesis química , Aminoácidos/farmacocinética , Animales , Ácido Aspártico/química , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacocinética , Perros , Evaluación Preclínica de Medicamentos , Ésteres/síntesis química , Ésteres/farmacocinética , Humanos , Concentración 50 Inhibidora , Oligopéptidos/química , Oligopéptidos/farmacocinética , Unión Proteica , Receptores de Vitronectina/metabolismo , Relación Estructura-ActividadRESUMEN
Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, alpha(v)beta(3). The use of the 5,6,7,8-tetrahydro[1,8]naphthyridine group as a potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in alpha(IIb)beta(3) antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.
Asunto(s)
Oligopéptidos/farmacología , Receptores de Vitronectina/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Unión Competitiva , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Conformación Molecular , Imitación Molecular , Oligopéptidos/síntesis química , Oligopéptidos/química , Osteoporosis/prevención & control , Agregación Plaquetaria/efectos de los fármacos , Receptores de Vitronectina/metabolismo , Relación Estructura-ActividadRESUMEN
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared incorporating various beta-amino acids as aspartic acid mimetics. Modification of the beta-alanine 3-substituents alters the potency and physicochemical properties of these receptor antagonists and in some cases provides orally bioavailable alpha(v)beta(3) inhibitors.