David G. Melillo

A Receptor in Pituitary and Hypothalamus That Functions in Growth Hormone Release

Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.

A practical synthesis of (±)-thienamycin

Abstract An efficient and operationally simple synthesis of (±)-thienamycin is described.

Further studies on the acetonedicarboxylate route to thienamycin—stereochemical inversion at the lactone stage.

Abstract Stereochemical inversion of an easily prepared δ-lactone has culiminated in the preparation of a key intermediate for the synthesis of thienamycin.

A convenient method for [14C] carbonylation reactions

A simple, efficient method for generation of 14CO from Ba14CO3 has been developed. Reduction of 14CO2 using LiBEt3H gave [14C] formate in good yield which was treated with conc. H2SO4 to effect dehydration to 14CO. Through direct attachment of a reaction vessel containing aryl substrate and Pd(0) catalyst,[14C]carbonylation reactions were performed without the use of a mercury transfer pump. [14C]Carbonylation reactions using 14CO generated in this manner have been shown to proceed in good yield with a variety of substrates. Copyright

Efficient utilization of [14C]carbon dioxide as a phosgene equivalent for labeled synthesis

Abstract Addition of one equivalent [14C]carbon dioxide to primary or secondary amines in the presence of ternary base, followed by reaction of the resulting [14C]carbamate salt with phosphorus oxychloride or thionyl chloride, represents a cost effective alternative to labeled phosgene.

Suzuki Cross-Coupling for the incorporation of labeled methyl groups onto aryl halides. A synthesis of [14C]tosyl chloride and its use in the synthesis of [14C]L-738,167

A synthesis of [4-methyl]-14C]tosyl chloride (2) has been developed which utilizes a Suzuki Cross-Coupling reaction between 4-iodophenylsulfonic acid and a labeled methyl borinate as the key step. This process avoids the poor regioselectivity typically attendant with aromatic sulfonation procedures. We now describe the use of this [14C]tosyl chloride in the synthesis of the orally active fibrinogen receptor antagonist L-738,167 (1). Copyright

The synthesis of HIV reverse transcriptase inhibitors [14C]L-697,661, [14C]L-697,639, [14C]L-702,007

The synthesis of three carbon-14 labeled reverse transcriptase inhibitors has been accomplished by elaboration of a common intermediate, 5-ethyl-6-methyl-3-amino-2-(1H)-[4- 14 C] -pyridinone (7). Ethyl [l- 14 C]formate, prepared by esterification of sodium [ 14 C]formate, was combined with 2-pentanone under basic conditions to afford 3-[ 14 C]carboxaldehyde-2-pentanone sodium salt (2). The pyridinone ring was constructed by condensation of 2 with nitro acetamide 4. Reduction of the nitro group afforded 5-ethyl-6-methyl-3-amino-2-(1H)-[4- 14 C]-pyridinone (7)(specific activity 54 mCi/mmol). Subsequent alkylation of 7 provided the desired reverse transcriptase inhibitors [ 14 C]L-697,661, [ 14 C]L-697,639. and [ 14 C]L-702.007.

Synthesis, stability, and radiolytic decomposition of carbon‐14 labeled MK0677

MK0677 is an orally active growth hormone secretagogue. The crystallized carbon-14 labeled material was found to undergo radiolytic decomposition via a peroxide intermediate which resulted in loss of the benzyl group. The rate was diminished when the tracer was crystallized from nitrogen-degassed solvents. Storage stability was best in aqueous ethanol.

Carbon-14 labeling of a potential new immunoregulant agent

A carbon-14 labeled version of the ascomycin analog 1, a potential new immunosuppressant agent, was synthesized for utilization in animal and human drug metabolism studies. In order to place the carbon-14 label at a metabolically stable position, it was necessary to modify the established synthesis of a key intermediate. [ 14 C]1 is prepared by a highly chemoselective alkylation of ascomycin at the C-32 hydroxy position with a carbon-14 labeled imidazolyl trichloroimidate side chain 2. Carbon-14 was efficiently incorporated in 2 through carboxylation of an imidazole C-2 lithiate with [ 14 C]carbon dioxide.