title: 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.
abstract: 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, α4β1 and α4β7 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.
authors: Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. sidduria@yahoo.com
authors: Achyutharao
authors: A
authors: Sidduri
authors: Jefferson W
authors: JW
authors: Tilley
authors: Jianping
authors: J
authors: Lou
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 / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D051379:Mice; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004952:Esters; D039041:Integrin alpha4beta1; D016023:Integrins; D011355:Prodrugs; D011743:Pyrimidines; C071777:integrin alpha4beta7; D010649:Phenylalanine