Thomas M. Jacks

Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues.

A new class of potent, orally active phenyl piperazine-based GH secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substituent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4 and 1, respectively. The best of these compounds, 18 (EC50 = 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.

Synthesis and biological activities of spiroheterocyclic growth hormone secretagogues

The synthesis and biological activities of a series of spiroheterocyclic growth hormone secretagogues are reported. Modification of the spiroindane part-structure of the prototypal secretagogue L-162,752 revealed that the spiroindane could be replaced with spirobenzodihydrothiophen derivatives to enhance not only in vitro potency but also oral activity. In this study non-aromatic D-2-amino-4-cyclohexylbutanoic analogs (8a-8d) were also identified to be active secretagogues.

Analogs of the orally active growth hormone secretagogue L-162,752

Abstract A series of spiroindane growth hormone secretagogues that vary in their amino side chains is reported. Variations in these side chains markedly affect growth hormone release in vitro and in vivo . The best side chain in this series of secretagogues is α-methylalanine. L-162,752 not only stimulated GH release from rat pituitary cells, but also induced GH release in dogs upon i.v. and p.o. administration.

Peptidomimetic growth hormone secretagogues: synthesis and biological activities of analogs varied at the indole nucleus of the prototypical spiropiperidine L-162,752

Abstract SAR studies around the indole nucleus of the prototypical peptidomimetic L-162,752 revealed that the D-Trp could be replaced with 3-phenylpropyl-D-glycine and O-benzyl-D-serine to provide secretagogues with comparable intrinsic activity but with significantly better oral activity in dogs. Use of dimethyl β-alanine amino side-chains led to a considerable loss of activity in the D-homophenylalanine and O-benzyl-D-serine series.

BENZOLACTAM GROWTH HORMONE SECRETAGOGUES : CARBOXAMIDES AS REPLACEMENTS FOR THE 2'-TETRAZOLE MOIETY OF L-692,429

Abstract A variety of 2′-carboxamides was investigated as replacements for the 2′-tetrazole moiety of L-692,429. Investigation of the structure-activity relationships of the carboxamide series determined that primary and secondary carboxamides are potent growth hormone secretagogues in vitro . L-700,653 ( 11 ) was identified as an orally active GH secretagogue in dogs.

Alendronate binds to tooth root surfaces and inhibits progression of feline tooth resorption: a pilot proof-of-concept study.

Tissue distribution, bioavailability, and efficacy of alendronate in preventing progression of resorption of teeth were evaluated in cats. [Butyl-4-14C-]-alendronate accumulates on subgingival tooth and alveolar bone surfaces adjacent to vascularized tissue resulting in concentration of the drug around tooth roots. Three cats were treated with a 0.03 mg/kg IV bolus of [butyl-4-14C-]-alendronate followed by blood, urine, and feces collection and euthanasia 24-hours later. Drug tissue distribution was accessed by autoradiography and sample combustion. To assess bioavailability, 12 cats were administered alendronate orally (3.0 or 9.0 mg/kg in water or 9.0 mg/kg in tuna water) and urine was collected for 24-hours. In these formulations, alendronate oral bioavailability in cats was approximately 3 %. In addition, 10 cats with radiographic evidence of pre-existing tooth resorption (14 affected teeth) were treated with vehicle or 3.0 mg/kg alendronate per os once weekly for 22-weeks and, then, 9.0 mg/kg per os twice weekly for 27-weeks in a random, masked study. Radiographic area of resorption was measured and progression scored every 3 to 4-months. In placebo-treated cats, resorption progressed in five of six teeth (+ 97 % average increase in area of resorption), whereas progression of resorption was seen in only three of eight affected teeth in alendronate-treated cats with a – 22 % average change (decrease) in area (P < 0.01 difference in number of teeth showing progression; P < 0.001 difference in area of resorption). Alendronate accumulated preferentially on subgingival tooth surfaces and adjacent alveolar bone and, at a dose of 9 mg/kg twice weekly, effectively slowed or arrested the progression of resorption.

The synthesis and activity of spiroindane growth hormone secretagogues

Abstract The synthesis and activities of a series of spiroindane growth hormone secretagogues is reported. Modification of the benzylic position of the spiroindane has resulted in a dramatic increase in potency resulting in subnanomolar peptidomimetic growth hormone secretagogues. In vivo data demonstrating the good oral activity of these analogs is reported.

Substituted bridged phenyl piperidines: orally active growth hormone secretagogues

A new series of growth hormone secretagogues have been discovered. The best compound, 26j, shows excellent ability to release growth hormone both in vitro and in vivo. The synthesis and biological activity of these compounds are discussed.

The design and synthesis of orally active short duration spiroindane growth hormone secretagogues

The design, synthesis, and activities of a series of short duration spiroindane growth hormone secretagogues are reported. Incorporation of a readily metabolized ester into the spiroindane benzylic position provided a series of highly potent orally active secretagogues with a short duration of action.

Phenyl piperidine-based orally active peptidomimetic agonists for somatostatin receptor subtype-2

Selective human somatostatin subtype-2 (hsst2) receptor agonists have received considerable attention recently since they may offer benefit in treating diabetes [1]. Specifically, sst2 activation inhibits growth hormone (GH) and glucagon release without much effect on the release of insulin. Cyclic peptide 1 and small molecule 2 [1] represent selective ligands for hsst2. In this paper we disclose orally active phenyl piperidine-based small molecule agonists which possess high selectivity towards hsst2.