ABSTRACT
Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.
Subject(s)
Drug Discovery , Epilepsy/drug therapy , Ion Channel Gating/drug effects , KCNQ2 Potassium Channel/metabolism , Piperidines/pharmacology , Pyrimidines/pharmacology , Animals , Cell Line , Dose-Response Relationship, Drug , Electroshock , Humans , KCNQ2 Potassium Channel/agonists , Microsomes/drug effects , Molecular Structure , Piperidines/administration & dosage , Piperidines/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
We report the synthesis of a series of [3.2.1]azabicyclic biaryl ethers as selective agonists of alpha3- and alpha6-containing nicotinic receptors. In particular, compound 17a from this series is a potent alpha3beta4 and alpha6/4beta4 receptor agonist in terms of both binding and functional activity. Compound 17a also shows potent in vivo activity in CNS-mediated animal models that are sensitive to antipsychotic drugs. Compound 17a may thus be a useful tool for studying the role of alpha3beta4 and alpha6/4beta4 nicotinic receptors in CNS pharmacology.
Subject(s)
Azabicyclo Compounds/chemistry , Nicotinic Agonists/chemistry , Receptors, Nicotinic/chemistry , Sulfonamides/chemistry , Azabicyclo Compounds/chemical synthesis , Azabicyclo Compounds/pharmacology , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
We describe a novel series of inhibitors of the type 1 glycine transporter (GlyT1) as an approach to relieving the glutamatergic deficit that is thought to underlie schizophrenia. Synthesis and SAR follow-up of a series of octahydro-cyclopenta[c]pyrrole derivatives afforded potent in vitro inhibition of GlyT1 as well as in vivo activity in elevating CSF glycine. We also found that a 3-O(c-pentyl), 4-F substituent may serve as a surrogate for the widely used 3-trifluoromethoxy group, suggesting its application as an isostere for future medicinal chemistry studies.
Subject(s)
Cyclopentanes/chemistry , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Pyrroles/chemistry , Animals , Cell Line , Cyclopentanes/pharmacology , Dogs , Glycine Plasma Membrane Transport Proteins/physiology , Humans , Microsomes/drug effects , Microsomes/physiology , Pyrroles/pharmacologyABSTRACT
Sulfonamides, exemplified by 3a, were identified as highly selective EP(2) agonists. Lead optimization led to the identification of CP-533536, 7f, a potent and selective EP(2) agonist. CP-533536 demonstrated the ability to heal fractures when administered locally as a single dose in rat models of fracture healing.
Subject(s)
Osteogenesis/drug effects , Pyridines/chemistry , Receptors, Prostaglandin E/agonists , Animals , Male , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Prostaglandin E/metabolism , Receptors, Prostaglandin E, EP2 Subtype , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
Heptanoic acid lactams, exemplified by 2, were identified as highly selective EP4 agonists via high throughput screening. Lead optimization led to the identification of lactams with a 30-fold increase in EP4 potency in vitro. Compounds demonstrated robust bone anabolic effects when administered in vivo in rat models of osteoporosis.
Subject(s)
Bone Density/drug effects , Bone Development , Bone and Bones/drug effects , Organ Size/drug effects , Ovariectomy , Receptors, Prostaglandin E/agonists , Animals , Female , Osteoporosis , Rats , Rats, Sprague-Dawley , Receptors, Prostaglandin E, EP4 SubtypeABSTRACT
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.
