RESUMO
A practical synthesis of capromorelin (1), a growth hormone secretagogue, is described that utilizes as a key step a crystallization-induced dynamic resolution (CIDR) of (±)-3a-benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3(3aH)-one [(±)-2] by L-tartaric acid salt formation, yielding (R)-2.L-tartaric acid in high chemical yield (>85%) and with diastereomeric excess (de) of â¼98%. Treatment of (R)-2.L-tartaric acid with ammonium hydroxide provided (R)-2 without loss of chiral purity. In situ generated (R)-2 was coupled with (R)-3-(benzyloxy)-2-(2-(tert-butoxycarbonyl)-2-methylpropanamido)propanoic acid [(R)-3] to give predominantly a single diastereomer of N-Boc-protected capromorelin [(1R,3aR)-4]. This process was used to prepare bulk quantities of capromorelin from (±)-2 to support preclinical toxicology studies.
Assuntos
Piperidinas/síntese química , Pirazóis/síntese química , Termodinâmica , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Pirazóis/químicaRESUMO
A series of ligands with varying heterocyclic cores and substituents that display a range of selectivity's (up to >100x) for ER-beta over ER-alpha are reported.
Assuntos
Receptor beta de Estrogênio/metabolismo , Compostos Heterocíclicos/farmacocinética , Linhagem Celular Tumoral , Cristalografia por Raios X , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/química , Compostos Heterocíclicos/síntese química , Humanos , Indicadores e Reagentes , Cinética , Ligantes , Moduladores Seletivos de Receptor Estrogênico/química , Relação Estrutura-AtividadeRESUMO
Two series of 6-hydroxy and 7-hydroxy tetrahydroisoquinolines were prepared. Evaluating a range of C-1, C-4, and N-substituents led to the discovery of ER alpha and ER beta selective analogs.
Assuntos
Moduladores Seletivos de Receptor Estrogênico/síntese química , Tetra-Hidroisoquinolinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/química , Receptor beta de Estrogênio/química , Feminino , Humanos , Concentração Inibidora 50 , Ligantes , Ligação Proteica , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese químicaRESUMO
New tert-butyl, picolyl and fluorinated analogues of capromorelin (3), a short-acting growth hormone secretagogue (GHS), were prepared as part of a program to identify long-acting GHSs that increase 24-h plasma IGF-1 levels. Compounds 4c and 4d (ACD LogD values >or=2.9) displayed extended plasma elimination half-lives in dogs, primarily due to high volumes of distribution, but showed weak GH secretagogue activities in rats (ED(50)s>10 mg/kg). A less lipophilic derivative 4 (ACD LogD=1.6) exhibited a shorter canine half-life, but stimulated GH secretion in two animal species. Repeat oral dosing of 4 in dogs for 29 days (6 mg/kg) resulted in a significant down-regulation of the post dose GH response and a 60 and 40% increase in IGF-1 levels relative to pre-dose levels at the 8- and 24-h post dose time points. Compound 4 (CP-464709-18) has been selected as a development candidate for the treatment of frailty.
Assuntos
Piperidinas/farmacocinética , Pirazóis/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Cães , Hormônio do Crescimento/efeitos dos fármacos , Substâncias de Crescimento/metabolismo , Meia-Vida , Interações Hidrofóbicas e Hidrofílicas , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Masculino , Piperidinas/administração & dosagem , Piperidinas/síntese química , Pirazóis/administração & dosagem , Pirazóis/síntese química , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin (5, CP-424391-18, hGHS-R1a K(i)=7 nM, rat pituicyte EC(50)=3 nM) and the des-methyl analogue 5c (hGHS-R1a K(i)=17 nM, rat pituicyte EC(50)=3 nM), increased plasma GH levels in an anesthesized rat model, with ED(50) values less than 0.05 mg/kg iv. Capromorelin showed enhanced intestinal absorption in rodent models and exhibited superior pharmacokinetic properties, including high bioavailabilities in two animal species [F(rat)=65%, F(dog)=44%]. This short-duration GHS was orally active in canine models and was selected as a development candidate for the treatment of musculoskeletal frailty in elderly adults.