315710-15-7

Upstream product

• 317356-27-7 tert-butyl (2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate 
• 203866-13-1 (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid 
• 99-76-3 methyl 4-hydroxylbenzoate 
• 317356-28-8 methyl 4-[1-(tert-butoxycarbonyl)-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoate 

Downstream Products

• 317364-42-4 C₂₈H₂₆Cl₂FN₃O₅ 
• 317356-71-1 C₂₈H₂₆BrClFN₃O₅ 
• 317356-77-7 C₂₉H₂₉BrFN₃O₅ 
• 317356-80-2 C₂₈H₂₆BrClFN₃O₅ 
• 317356-83-5 C₂₈H₂₆Br₂FN₃O₅ 
• 441713-50-4 methyl 4-[(4S)-fluoro-1-[2-(2-methylphenylamino)-6-benzoxazolylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate 
• 441713-94-6 methyl trans-4-[(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate 
• 1136835-94-3 methyl 4-[1-[3-chloro-4-[N'-(5-fluoro-2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate 
• 317364-39-9 methyl 4-[(2S,4S)-1-[(3-chloro-4-[N'-(2-methylphenyl)ureido]phenyl)acetyl]-4-fluoro-2-pyrrolidinylmethoxy]benzoate 

Relevant academic research and scientific papers

Discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido) phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid: An orally active, selective very late antigen-4 antagonist

We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3- indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-( 2S)-pyrrolidinylmethoxy] cyclohexanecarboxylic acid (14e) with potent activity (IC50 = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.

4-(Pyrrolidinyl)methoxybenzoic acid derivatives as a potent, orally active VLA-4 antagonist

A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50=1.6 nM each) and moderate lipophilicity (Log D=2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.