Dennis L. Bohn

Pharmacokinetic optimization of 3-amino-6-chloropyrazinone acetamide thrombin inhibitors. Implementation of P3 pyridine N-oxides to deliver an orally bioavailable series containing P1 N-benzylamides.

In this manuscript we demonstrate that a modification principally directed toward the improvement of the aqueous solubility (i.e., introduction a P3 pyridine N-oxide) of the previous lead compound afforded a new series of potent orally bioavailable P1 N-benzylamide thrombin inhibitors. An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation.

Renal clearance of uric acid in nonhuman primates

Abstract 1. 1. Uric acid clearance in Old World monkeys upon urate loading is greater than the simultaneously determined glomerular filtration rate except for tje bushbaby. 2. 2. All monkeys studied, except the spider monkey, possess liver uricase. In New World monkeys, uric acid is reabsorbed to varying degrees by the renal tubules except for the howler monkey, in which tubular secretion is seen. 3. 3. Apes (chimpanzee and gibbon) are devoid of uricase and avidly reabsorb filtered urate.

3-amino-4-sulfonylpyridinone acetamide and related pyridothiadiazine thrombin inhibitors.

We describe a series of highly potent and efficacious thrombin inhibitors based on a 3-amino-4-sulfonylpyridinone acetamide template. The functionally dense sulfonyl group stabilizes the aminopyridinone, conformationally constrains the 4-substituent, and forms a hydrogen bond to the insertion loop tyrosine OH. We also describe a related series of fused bicyclic dihydrothiadiazinedioxide derivatives, of which one had improved pharmacokinetics in dogs after oral dosing.