The blood glucose level lowering activity of [(acylamino)ethyl]benzoic acids, such as p-[2-(5-chloro-2-methoxy-benzamido)ethyl]benzoic acid (HB699, 2), is discussed in terms of binding at putative insulin-releasing receptor sites of pancreatic beta cells. The hypoglycemic potencies found for synthetic analogues of 2 indicate that high hypoglycemic activity is only found when a carboxyl group or a group that is readily oxidized to carboxyl in vivo, such as methyl, is attached to the aromatic ring of the phenethyl group. It is proposed that this carboxyl group is able to bind at the same receptor site as the SO2NHCONH group of the sulfonylurea drugs, such as tolbutamide (3). The role of the benzamide group in 2 was attributed to protein binding.

No abstract

Quinuclidines with a 3-biaryl substituent are a new class of potent, orally active squalene synthase (SQS) inhibitors. Variants around these rigid structures indicate key structural requirements for cationic SQS inhibitors. Thus the lower in vitro potency found for quinuclidines bearing 3-substituents, which did not overlay the biphenyl group of 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (2) (IC50 = 16 nM, rat microsomal SQS), implied a directional requirement for the 3-substituent. Similarly, the lower potency of the 3-terphenyl analogue 6 (IC50 = 370 nM) indicated size constraints for this substituent. In compounds with a linking group between the quinuclidine and biphenyl ring, linking groups of lower lipophilicity were less well tolerated (e.g., 17, CH2CH2, IC50 = 5 nM vs 19, NHCO, IC50 = 1.2 microM). Replacement of the distal phenyl ring of 2 with a more polar pyridine heterocycle caused a reduction in in vitro potency. In general, good in vivo activity in the rat was restricted to 3-hydroxy analogues, with the 3-[4-(pyrid-4-yl)phenyl] derivative 39 (IC50 = 161 nM) showing the best inhibition (following oral dosing) of cholesterol biosynthesis from mevalonate (ED50 = 2.7 mg/kg).

Novel 3-substituted quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure-activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted quinuclidine pharmacophore 18a-c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted quinuclidines, which were derived from a quinuclidine series previously known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhibition of OSC.

No abstract