Utilization of in vitro Caco-2 permeability and liver microsomal half-life screens in discovering BMS-488043, a novel HIV-1 attachment inhibitor with improved pharmacokinetic properties.
Optimizing pharmacokinetic properties to improve oral exposure is a common theme in modern drug discovery. In the present work, in vitro Caco-2 permeability and microsomal half-life screens were utilized in an effort to guide the structure-activity relationship in order to improve the pharmacokinetic properties of novel HIV-1 attachment inhibitors. The relevance of the in vitro screens to in vivo pharmacokinetic properties was first demonstrated with a number of program compounds at the early stage of lead optimization. The Caco-2 permeability, tested at 200 microM, was quantitatively predictive of in vivo oral absorption, with complete absorption occurring at a Caco-2 permeability of 100 nm/s or higher. The liver microsomal half-life screen, conducted at 1 microM substrate concentration, can readily differentiate low-, intermediate-, and high-clearance compounds in rats, with a nearly 1:1 correlation in 12 out of 13 program compounds tested. Among the >100 compounds evaluated, BMS-488043 emerged as a lead, exhibiting a Caco-2 permeability of 178 nm/s and a microsomal half-life predictive of a low clearance (4 mL/min/kg) in humans. These in vitro characteristics translated well to the in vivo setting. The oral bioavailability of BMS-488043 in rats, dogs, and monkeys was 90%, 57%, and 60%, respectively. The clearance was low in all three species tested, with a terminal half-life ranging from 2.4 to 4.7 h. Furthermore, the oral exposure of BMS-488043 was significantly improved (6- to 12-fold in rats and monkeys) compared to the prototype compound BMS-378806 that had a suboptimal Caco-2 permeability (51 nm/s) and microsomal half-life. More importantly, the improvements in preclinical pharmacokinetics translated well to humans, leading to a >15-fold increase in the human oral exposure of BMS-488043 than BMS-378806 and enabling a clinical proof-of-concept for this novel class of anti-HIV agents. The current studies demonstrated the valuable role of in vitro ADME screens in improving oral pharmacokinetics at the lead optimization stage.
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492, USA. yangz@bms.com
Zheng
Z
Yang
Lisa M
LM
Zadjura
Anthony M
AM
Marino
Celia J
CJ
D'Arienzo
Jacek
J
Malinowski
Christoph
C
Gesenberg
Pin-Fang
PF
Lin
Richard J
RJ
Colonno
Tao
T
Wang
John F
JF
Kadow
Nicholas A
NA
Meanwell
Steven B
SB
Hansel
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D004285:Dogs; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D007211:Indoles; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D019289:Pyruvic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D023581:HIV Fusion Inhibitors; D007211:Indoles; D010879:Piperazines; D019289:Pyruvic Acid; C509651:BMS-488043