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

Muro, Fumihito; Iimura, Soshi; Sugimoto, Yuuichi; Yoneda, Yasuko; Chiba, Jun; Watanabe, Toshiyuki; Setoguchi, Masaki; Iigou, Yutaka; Matsumoto, Keiko; Satoh, Atsushi; Takayama, Gensuke; Taira, Tomoe; Yokoyama, Mika; Takashi, Tohru; Nakayama, Atsushi; Machinaga, Nobuo

doi:10.1021/jm901154c

Cited by 25 publications

(26 citation statements)

References 45 publications

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“…This new approach efficiently provided 1 in 17% overall yield compared with the reported procedure (3.3% overall yield). 1) The synthesized compound 1 had an inhibition potency with an IC 50 value of 5.9 nM in VLA-4/vascular cell adhesion molecule-1 (VCAM-1) binding assay, which was in line with the previously reported value (5.4 nM). 1)…”

supporting

confidence: 89%

“…The N-benzyloxycarbonyl group of 17 was removed by hydrogenolysis to give 2b. Subsequent condensation of 2b with arylacetic acid 8 1) and acidic hydrolysis of the tert-butyl ester group of the resulting amide successfully provided 1 ([a] D 25 Ϫ34.7°, Ͼ99% ee) 9) in 74% yield from 17. This new approach efficiently provided 1 in 17% overall yield compared with the reported procedure (3.3% overall yield).…”

mentioning

confidence: 99%

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A Novel Synthetic Approach to Very Late Antigen-4 Antagonist trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic Acid via tert-Butyl trans-[(4S)-Methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate as a Key Intermediate

Chiba

Machinaga

2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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supporting

confidence: 89%

mentioning

confidence: 99%

A Novel Synthetic Approach to Very Late Antigen-4 Antagonist trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic Acid via tert-Butyl trans-[(4S)-Methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate as a Key Intermediate

Chiba

Machinaga

2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…A couple of antagonists share the same profile than CT7758 with much lower total plasma clearance and lower volume of distribution in dog than in rodent. The most striking examples include compound 14e (trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid) (Muro et al, 2009) with a CL of 19.3, 1.7, 1.8 ml/min/kg in rat, dog, and monkey, respectively. The volume of distribution follows the same ranking with 1.22, 0.16, and 0.22 l/kg, respectively.…”

Section: Discussionmentioning

confidence: 99%

Cross-Species Differences in the Preclinical Pharmacokinetics of CT7758, an α4β1/α4β7 Integrin Antagonist

et al. 2015

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CT7758, a carboxylate containing a4b1/a4/b7 integrin antagonist, was characterized for its pharmacokinetic profile in various in vitro and in vivo assays in support of clinical development. The oral bioavailability of CT7758 was 4% in mice, 2% in rats, 7-55% in dogs, and 0.2% in cynomolgus monkeys. The low bioavailability in rodents and monkey results from low intestinal absorption as evidenced by a low fraction absorbed in the rat portal vein model (3%), low-tomedium permeability in Caco-2 cells (£1.3 3 10 26 cm/s) with evidences of polarized efflux, and high polar surface area (104 Å). In rodents and cynomolgus monkeys, the total plasma clearance was moderate to high ( ‡50% hepatic blood flow Q H ) and associated with a short elimination half-life (£1 hour). This contrast with the dog data which showed a much lower clearance (6% Q H ) and a longer t 1/2 (2.4 hours). The volume of distribution (V z ) also varied significantly across species with value of 5.5, 2.8, 0.24, and 0.93 l/kg in mouse, rat, dog, and cynomolgus monkey, respectively. In vitro assays demonstrated that active hepatic uptake accounted for most of the in vivo clearance and was the source of the large species variability. In vitro uptake assays predicted a total plasma clearance in humans in the low range (33% Q H ), a finding subsequently confirmed in the clinic. Assays in OAPT1B1-transfected cells demonstrated active uptake transport through this transporter. The prospect of limited absorption in human prompted the synthesis an ethyl ester prodrug, CDP323, which demonstrated higher in vitro permeability, increased oral bioavailability, as well as efficient in vivo release of its active moiety CT7758.

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“…12) Theoretical unbound fraction (fu) was calculated from the activity ratio based on the theoretical equation in the inhibition scheme (see Results and Discussion, Chart 2).…”

Section: Methodsmentioning

confidence: 99%

“…As model compounds, inhouse very late antigen-4 (VLA-4) antagonists were used because the pharmacokinetics of VLA-4 antagonists, i.e., the interindividual variability/clearance was reported to be strongly influenced by protein binding. 11,12) These antagonists were acidic compounds that have a carboxylic acid and three kinds of derivatives, in which its basic structure is shown in Chart 1.…”

mentioning

confidence: 99%

Evaluation of Serum Protein Binding by Using in Vitro Pharmacological Activity for the Effective Pharmacokinetics Profiling in Drug Discovery

Kawai

Fujii

Akimoto

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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The affinity of a drug to serum proteins has a major clinical significance on both pharmacokinetics and pharmacodynamics in vivo. [1][2][3] It is well known that unbound drug to serum protein is excreted from the body by diverse elimination processes, while bound drug constantly serves to recruit unbound drug to the plasma concentration. Consequently, a high level of protein binding prolongs the duration of total drug concentration in blood, whereas protein binding reduces the unbound fraction (fu) and therefore the pharmacological activity of a drug. Thus, the degree of protein binding is a key factor in the delicate balance between the intended pharmacological activity and potential unintentional effects of the drug.According to the recent advances in high-throughput screening technology, [4][5][6] multifaceted approaches such as pharmacokinetics, toxicity and physicochemical properties are now becoming more important in the drug discovery process. Namely, the strategy to select a drug candidate shifts from a bias toward the pharmacological activity to a balance in the pleiotropic properties including ADME (absorption, distribution, metabolism, excretion), physicochemical parameter and so on. An early survey of the protein binding level is one of the significant evaluations, as well as other ADME parameters. In particular, the evaluation of the effect of protein binding on the pharmacological activity is essential information for drug design.Many reports concerned with the assessment of protein binding and simplified approaches for the determination of protein binding are being considered. The conventional methods such as equilibrium dialysis, 7) surface plasmon resonance (SPR),3) ultrafiltration, 8) ultracentrifugation 9) and so on were improved and/or developed as high-throughput screening technology.In view of this, we need to pay attention to the difference of affinity to serum protein such as specific and nonspecific binding. 7-Hydroxystaurosporine was reported to be nonspecifically bound to rat a 1 -acid glycoprotein (rAGP), 10) whereas its protein binding to human AGP (hAGP) was the sum of specific and nonspecific binding. The pharmacokinetics of 7-hydroxystaurosporine in humans have shown a very distinctive feature, i.e., low clearance/distribution volume and a long half-life in contrast to the experimental animals. Therefore, Fuse et al. showed that the specific high affinity binding to hAGP is one of the reasons for unusual pharmacokinetics of 7-hydroxystaurosporine in clinical studies. 10) Consequently, the difference of affinity, as well as the extent of bound was suggested to play a key role in drug pharmacokinetics and/or the pharmacological activity.The concentration dependence of percent bound, i.e., Scatchard plot analysis by equilibrium dialysis, has been studied in order to examine the difference of affinity. However, feasibility of the conventional methods relies either on a separation of bound and unbound drugs or on the physicochemical properties of drugs such as adsorption to membrane/th...

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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

Cited by 25 publications

References 45 publications

Cross-Species Differences in the Preclinical Pharmacokinetics of CT7758, an α4β1/α4β7 Integrin Antagonist

Evaluation of Serum Protein Binding by Using in Vitro Pharmacological Activity for the Effective Pharmacokinetics Profiling in Drug Discovery

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