Brad D. Maxwell

Fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), metabolic dysfunction-associated steatohepatitis (MASH), and kidney fibrosis represent a major unmet medical need. IPF patients have a mean survival of only 2–5 years, and despite this critical need, only two drugs have been approved in the past decade. These therapies offer limited efficacy and poor tolerability, underscoring the need for better options. Targeting αV integrins has emerged as a promising strategy, supported by strong preclinical data. While αVβ1/6 inhibitors are in clinical trials, our approach focused on developing pan-αV inhibitors with selectivity over αVβ8 and αIIbβ3 and oral pharmacokinetics. Through lead optimization, we identified compound 14, a potent inhibitor of αVβ1, αVβ3, αVβ5, and αVβ6, with high selectivity, oral bioavailability, and low IV clearance. In a mouse unilateral ureteral obstruction model, oral dosing of 14 (10 mg/kg/day for 8 days) reduced total collagen by 25% versus vehicle.

Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a ‘deuterium switch’ approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed.

The International Consortium for Innovation & Quality (IQ) in Pharmaceutical Development recently established a Working Group focused on the development of a guidance to address Deuterated Active Pharmaceutical Ingredients. Deuteration of an Active Pharmaceutical Ingredient (API) in some cases can retard and/or alter API metabolism by exploiting the primary kinetic isotope effect.^1,2 Several deuterated APIs have entered into the clinic, and one has recently been approved.³ In most cases, it is very difficult to nearly impossible to synthesize a 100% isotopically pure compound. This raises synthetic, analytical, and regulatory questions that warrant a science‐based assessment and recommendations for synthetic methods, analytical methods, and specifications. A cross functional team of scientists with expertise in isotope chemistry, process chemistry, analytical chemistry, and drug metabolism and pharmacokinetics have been meeting under the auspices of IQ to define and address these questions. This paper strives to frame chemistry, manufacturing, and controls challenges.

BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) enzyme (IC₅₀ = 2.3 nM) with >10,000-fold selectivity over 11β-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED₅₀ = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED₅₀ = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED₅₀ = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.

The isotopic labeling of molecules for agrichemical and pharmaceutical uses is becoming more challenging as molecules become larger, involve more stereochemistry, and as intellectual property rights become more complex. As such, isotope chemists need to continually add new isotopic methods to their armamentarium to successfully label complex molecules with carbon‐13 and carbon‐14. Recently, there has been a surge in the use of radicals to form new carbon‐carbon bonds and for the incorporation of functional groups which can be used to incorporate isotopically labeled carbons. This review will describe some potential new radical methods for incorporating isotopically labeled carbon into complex molecules or into substrates that can be attached to late stage intermediates to generate labeled products.

Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa K_i = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme (IC₅₀ 3.0 nM) with >10000-fold selectivity over human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED₅₀ 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11β-HSD1 enzyme for the first 12 h period after dosing followed by an “inhibition holiday” so that the potential for hypothalamic–pituitary–adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.

PEGylation is a proven approach to prolonging the duration of action and enhancing biophysical solubility and stability of peptides. 4‐Acetylphenylalanine is a novel amino acid with a ketone side chain that is uniquely reactive in proteins. The ketone functionality can react with an aminooxy functionalized polyethyleneglycol polymer to form a stable oxime adduct of the protein. One concern with using unnatural amino acids, such as 4‐acetylphenylalanine, is the possibility of it being cleaved from the peptide and becoming incorporated into endogenous proteins. To determine whether this occurs, an in vitro experiment to assess the cell viability and amino acid incorporation into endogenous proteins using primary male rat hepatocytes in the presence of [¹⁴C]4‐acetylphenylalanine, 4 or [¹⁴C(U)]L‐phenylalanine was conducted. [¹⁴C]4‐acetylphenylalanine, 4 was prepared in 2 radiochemical steps from [1‐¹⁴C]acetyl chloride in an overall 8% radiochemical yield and in 99.9% radiochemical purity. The results showed that there was no evidence of carbon‐14 incorporation into hepatocyte endogenous proteins with [¹⁴C]pAcF and there was no difference between it and L‐phenylalanine in cell viability assessments at any of the concentrations studied between 0.1 and 1000 μM.

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS‐816336 as an inhibitor of 11β‐hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of carbon‐14 labeled material was required for use in metabolic profiling. [Phenyl‐¹⁴C(U)]BMS‐816336 was synthesized in 8 steps and 22% radiochemical yield from commercially available [¹⁴C(U)]bromobenzene. The radiochemical purity of [phenyl‐¹⁴C(U)]BMS‐816336 was 100% having a specific activity of 84.4 μCi/mg or 28.8 mCi/mmol for a total of 8.9 mCi. It was also necessary to synthesize [¹³C₆]BMS‐816336 for use as a liquid chromatography/mass spectrometry standard. [¹³C₆]BMS‐816336 was also prepared in 8 labeled steps in 26% yield from [¹³C₆]bromobenzene.

A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF₃ to the pyrrolidine improves the human GPR40 binding K_i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both G_q-coupled intracellular Ca²⁺ flux and G_s-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.