title: Identification of N-acyl 4-(3-pyridonyl)phenylalanine derivatives and their orally active prodrug esters as dual acting α4β1 and α4β7 receptor antagonists.
abstract: 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.
authors: Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. tilleyjk@optonline.net
authors: Jefferson W
authors: JW
authors: Tilley
authors: Achyutharao
authors: A
authors: Sidduri
authors: Jianping
authors: J
authors: Lou
authors: Gerry
authors: G
authors: Kaplan
authors: Nadine
authors: N
authors: Tare
authors: Gary
authors: G
authors: Cavallo
authors: Karl
authors: K
authors: Frank
authors: Anjula
authors: A
authors: Pamidimukkala
authors: Duk Soon
authors: DS
authors: Choi
authors: Louise
authors: L
authors: Gerber
authors: Aruna
authors: A
authors: Railkar
authors: Louis
authors: L
authors: Renzetti
mesh_terms: D000818:Animals; D004285:Dogs; D004952:Esters / Q000097:blood / Q000494:pharmacology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D051379:Mice; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
chemical_list: D004952:Esters; D039041:Integrin alpha4beta1; D016023:Integrins; D011355:Prodrugs; C071777:integrin alpha4beta7; D010649:Phenylalanine