Abstract
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.
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