ABSTRACT
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.
Subject(s)
Piperidines/chemical synthesis , Pyrazoles/chemical synthesis , Thermodynamics , Crystallography, X-Ray , Models, Molecular , Molecular Structure , Piperidines/chemistry , Pyrazoles/chemistryABSTRACT
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.
Subject(s)
Estrogen Receptor beta/metabolism , Heterocyclic Compounds/pharmacokinetics , Cell Line, Tumor , Crystallography, X-Ray , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/chemistry , Heterocyclic Compounds/chemical synthesis , Humans , Indicators and Reagents , Kinetics , Ligands , Selective Estrogen Receptor Modulators/chemistry , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Selective Estrogen Receptor Modulators/chemical synthesis , Tetrahydroisoquinolines/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Estrogen Receptor alpha/chemistry , Estrogen Receptor beta/chemistry , Female , Humans , Inhibitory Concentration 50 , Ligands , Protein Binding , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity Relationship , Tetrahydroisoquinolines/chemical synthesisABSTRACT
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.
Subject(s)
Dipeptides/chemical synthesis , Dipeptides/pharmacology , Growth Hormone/metabolism , Piperidines/chemical synthesis , Piperidines/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Animals , Cells, Cultured , Chemical Phenomena , Chemistry, Physical , DNA, Complementary/metabolism , Dipeptides/pharmacokinetics , Dogs , Drug Design , Female , Half-Life , Humans , Indicators and Reagents , Indoles/pharmacology , Magnetic Resonance Spectroscopy , Piperidines/pharmacokinetics , Pituitary Gland/cytology , Pituitary Gland/drug effects , Pituitary Gland/metabolism , Pyrazoles/pharmacokinetics , Rats , Rats, Sprague-Dawley , Rats, Wistar , Solubility , Spiro Compounds/pharmacologyABSTRACT
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.
