1. 3-Mercaptopicolinic acid (SK&F 34288) inhibited gluconeogenesis in vitro, with lactate as substrate, in rat kidney-cortex and liver slices. 2. In perfused rat livers, gluconeogenesis was inhibited when lactate, pyruvate or alanine served as substrate, but not with fructose, suggesting pyruvate carboxylase or phosphoenolpyruvate carboxylase as the site of inhibition. No significant effects were evident in O(2) consumption, hepatic glycogen, urea production, or [lactate]/[pyruvate] ratios. 3. A hypoglycaemic effect was evident in vivo in starved and alloxan-diabetic rats, starved guinea pigs and starved mice, but not in 4h-post-absorptive rats. 4. In the starved rat the hypoglycaemia was accompanied by an increase in blood lactate. 5. A trace dose of [(14)C]lactate in vivo was initially oxidized to a lesser extent in inhibitor-treated rats, but during 90min the total CO(2) evolved was slightly greater. The total amount of the tracer oxidized was not significantly different from that in the controls.

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A series of substituted 2-arylthiazolo[3,2-a]pyridinium salts (1a-q) was prepared by known methods and tested for hypoglycemic activity in 48-h fasted rats. Two compounds, 2-phenylthiazolo- and 8-methyl-2-phenythiazolo[3,2-a]pyridinium perchlorate (1a and 1q), showed consistent hypoglycemic activity in this screen, demonstrating that a high degree of structural specificity was required for hypoglycemic activity. At higher doses the hypoglycemic activity of 1a and 1q was associated with elevated levels of hepatic triglycerides.

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Phenacyl-riphenylphosphorane (1a) and several analogs substituted in the meta position of the phenacyl group lowered blood glucose levels in 48-hr fasted rats. The corresponding phosphonium salts had comparable hypoglycemic activity. Two compounds (1a and 1b) were also hypoglycemic in fed rats, but hypoglycemia could not be elicited in another species.

A series of S-alkanoyl and benzoyl derivatives of 3-mercaptopicolinic acid (3-MPA) was prepared and studied for hypoglycemic activity. Three alkanoyl derivatives (propionyl, pivaloyl, and 1-adamantanecarbonyl, 19-21) were prepared with increasing bulk around the thio ester bond. The benzoyl derivatives contained aromatic substituents chosen from a sigma-pi cluster chart so that the esters prepared had a wide range of electronic and solubility properties. In general, compounds with substituents which increased lipid solubility [p-chlorobenzoyl (4), p-trifluoromethylbenzoyl (6), and pivaloyl (20)] had the greatest potency at a dose of 300 mg/kg. Hydrolysis rates, measured at pH 6 and 8, indicated that in vivo breakdown to 3-MPA probably did not account for the observed hypoglycemic activity of the esters. 4, 6, and 20 were less potent than 3-MPA in comparative dose range studies.

The brain of the young rat contains appreciable amounts of desmosterol (24‐dehydrocholesterol). The peak desmosterol concentration is seen during the first week of life and only traces of this sterol are found at 21 days. The spinal cord also contains some desmosterol. Rat brain desmosterol is distributed in the white matter, gray matter and cerebellum and occurs in the same proportion to cholesterol in each of these brain fractions. Rat brain contains a small amount of sterol ester but no appreciable amounts of desmosterol are present in this fraction.Studies carried out in intact animals injected either intraperitoneally or intracerebrally with mevalonic acid‐2‐14C or glucose‐U‐14C indicate the biosynthetic origin or brain desmosterol. Rat brain slices (1舑20 day old) incubated in suitably fortified medium convert sodium acetate‐2‐14C and glucose‐U‐14C to desmosterol, whereas brain slices from adult rats yielded no radioactive desmosterol under similar conditions. When labeled desmosterol was incubated with young rat brain slices, it was converted to cholesterol.When pregnant rats were treated with triparanol (20 mg/kg/day) during the course of their pregnancy, they either resorbed the fetuses or gave birth to small, stillborn litters. The brains of the progeny of triparanol treated mothers contained large amounts of desmosterol as well as another sterol which may be ख7,24‐cholestadiene‐3ॆ‐ol.