Identification of N-acyl 4-(3-pyridonyl)phenylalanine derivatives and their orally active prodrug esters as dual acting α4ß1 and α4ß7 receptor antagonists.

From a series of N-acyl 4-(3-pyridonyl)phenylalanine derivatives of 4, the trifluoromethyl derivative 28 was identified as a potent, dual acting alpha4 integrin antagonist with activity in primate models of allergic asthma. Investigation of a series of prodrug esters led to the discovery of the morpholinopropyl derivative 48 that demonstrated good intestinal fluid stability, solubility and permeability. Compound 48 gave high blood levels of 28 when dosed orally in cynomolgus monkeys. Surprisingly, hydrolysis of 48 was rapid in liver microsomes from the pharmacological species, mouse, rat and monkey, but slow in dog and human; in vivo studies also indicated there was prolonged exposure to unchanged prodrug in dogs.

Identification of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives and their orally active prodrug esters as dual-acting alpha4-beta1 and alpha4-beta7 receptor antagonists.

N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against α4-integrins. Several derivatives were identified as very potent dual-acting α4-integrin, α4ß1 and α4ß7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting α4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates.

2,3-Disubstituted acrylamides as potent glucokinase activators.

The phenylacetamide 1 represents the archtypical glucokinase activator (GKA) in which only the R-isomer is active. In order to probe whether the chiral center could be replaced, we prepared a series of olefins 2 and show in the present work that these compounds represent a new class of GKAs. Surprisingly, the SAR of the new series paralleled that of the saturated derivatives with the exception that there was greater tolerance for larger alkyl and cycloalkyl groups at R(2) region in comparison to the phenylacetamides. In normal Wistar rats, the 2,3-disubstituted acrylamide analog 10 was well absorbed and demonstrated robust glucose lowering effects.