Discovery and Development of Highly Potent and Orally Bioavailable Nonpeptidic αβ Integrin Inhibitors.

A series of 3-aryl(()-3-fluoropyrrolidin-1-yl)butanoic acids were developed as potent orally bioavailable αβ integrin inhibitors. Starting from a zwitterionic peptidomimetic series optimized for inhaled administration, the balancing of potency and passive permeability to achieve suitable oral agents through modification and exploration of aryl substituents and p of the central cyclic amine is described. ()-4-(()-3-Fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-3-(3-(2-methoxyethoxy)phenyl)butanoic acid was found to have highly desirable oral pharmacokinetic profiles in rat, dog, and minipig, with low to moderate clearance (26%, 7%, and 18% liver blood flow, respectively), moderate volumes of distribution (3.

Replacement of Less-Preferred Dipolar Aprotic and Ethereal Solvents in Synthetic Organic Chemistry with More Sustainable Alternatives.

Dipolar aprotic and ethereal solvents comprise just over 40% of all organic solvents utilized in synthetic organic, medicinal, and process chemistry. Unfortunately, many of the common "go-to" solvents are considered to be "less-preferable" for a number of environmental, health, and safety (EHS) reasons such as toxicity, mutagenicity, carcinogenicity, or for practical handling reasons such as flammability and volatility. Recent legislative changes have initiated the implementation of restrictions on the use of many of the commonly employed dipolar aprotic solvents such as dimethylformamide (DMF) and -methyl-2-pyrrolidinone (NMP), and for ethers such as 1,4-dioxane.

Discovery of ( S)-3-(3-(3,5-Dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αβ Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis.

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αβ, αβ, αβ, αβ, and αβ integrins. Numerous analogs with high affinity and selectivity for the αβ integrin were identified.