Bradley W. Caprathe

The design, synthesis, and pharmacological properties of a novel type of 4-(1,2,5,6-tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamine with dopaminergic properties are described. In particular, 4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine (4c, PD 118440) and its allyl analogue (4i, PD 120697) have been identified as orally active dopamine (DA) agonists with pronounced central nervous system effects in tests that include [3H]-haloperidol and [3H]-N-propylnorapomorphine binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. The DA autoreceptor selectivity of these heterocyclic analogues of 3-(1-propyl-3-piperidinyl)phenol (3-PPP) was also evaluated. In this series, DA agonist activity was found to be highly dependent on the size of the N-alkyl substituent, the saturation level of the six-membered ring, and the mode of attachment of the 2-aminothiazole ring.

A series of 2-amino-4H-3,1-benzoxazin-4-ones have been synthesized and evaluated as inhibitors of the complement enzyme C1r. C1r is a serine protease at the beginning of the complement cascade, and complement activation by beta-amyloid may represent a major contributing pathway to the neuropathology of Alzheimer's disease. Compounds such as 7-chloro-2-[(2-iodophenyl)-amino]benz[d][1,3]oxazin-4-one (32) and 7-methyl-2-[(2-iodophenyl)amino]benz[d][1,3]oxazin-4-one (37) show improved potency compared to the reference compound FUT-175. Many of these active compounds also possess increased selectivity for C1r compared to trypsin and enhanced hydrolytic stability relative to 2-(2-iodophenyl)-4H-3,1-benzoxazin-4-one (1).

A series of dihydro-1H-pyrrolizine-3,5(2H,6H)-diones were synthesized and evaluated for their ability to reverse electroconvulsive shock (ECS) induced amnesia in mice. Among the structure-activity relationships explored were the effects of ring size, the presence of heteroatoms (sulfur) in the ring system, and the introduction of alkyl substituents. The optimal ring size for the bicyclic system was 5.5 with dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (3), although some activity was present in the corresponding 5.6 [hexahydro-3,5-indolizinedione (7)] and 6.6 [tetrahydro-2H-quinolizine-4,6(3H,7H)-dione (9)] analogues. Replacement of the C-1 carbon atom in compound 3 with a sulfur [dihydropyrrolo[2,1-b]thiazole-3,5(2H,6H)-dione (10)] abolished activity, and the introduction of methyl groups resulted in poorer biological profiles except when the substitution was made at the 7a position [dihydro-7a-methyl-1H-pyrrolizine-3,5(2H,6H)-dione (4)]. In several instances, hydrolysis of the parent bicyclic compound was carried out to furnish the corresponding lactam acids, which were further derivatized. Several exhibited interesting activity, especially the 5-oxo-2-pyrrolidinepropanoic acid derivatives such as 5-oxo-2-pyrrolidinepropanoic acid (12), 5-oxo-2-pyrrolidinepropanoic acid phenylmethyl ester (17), 5-oxo-2-pyrrolidinepropanoic acid (3-chlorophenyl)methyl ester (20), N-4-pyridyl-5-oxo-2-pyrrolidinepropanoic acid amide (25), and N-(2,6-dimethylphenyl)-5-oxo-2-pyrrolidinepropanoic acid amide (27). Compound 3 (CI-911; rolziracetam) was also observed to improve performance on a delayed-response task in aged rhesus monkeys and was selected for evaluation in cognitively impaired human subjects on the basis of its biological profile and a wide margin of safety in animals.