GLP-1 receptor agonist combinations and use thereof for increasing weight loss while improving muscle mass and strength

Abstract

Disclosed are methods of improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy, reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength in a patient being treated with a GLP-1 receptor agonist, by administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof. Combinations of a GLP-1 receptor agonist and a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy, reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength in a patient are also provided.

Description

GLP-1 RECEPTOR AGONIST COMBINATIONS AND USE THEREOF FOR INCREASING WEIGHT LOSS WHILE IMPROVING MUSCLE MASS AND STRENGTH CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional application number 63 / 710,584, filed on October 22, 2024, the entire contents of which are hereby incorporated by reference herein. FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with Government support under contracts R44AR069400, R44CA277853, and R44DK142200 awarded by the National Institutes of Health. The Government has certain rights in the invention. FIELD OF THE INVENTION

[0003] The invention relates to methods of improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy, reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength in a patient being treated with a GLP-1 receptor agonist, using combination therapy of the GLP-1 receptor agonist and a compound of formula (I)or a pharmaceutically acceptable salt thereof. The invention also relates to combinations of the compound of formula (I) or pharmaceutically acceptable salt thereof with a GLP-1 receptor agonist, and uses thereof. BACKGROUND

[0004] Despite growing popularity of glucagon-like peptide-1 (GLP-1) receptor agonists as weight loss drugs, the weight loss realized on such drugs is frequently accompanied by significant muscle loss and weakness, which can have deleterious short-term and long-term effects. For example, it has been reported that semaglutide trials found 39–40% of weight lost on GLP-1 receptor agonists was lean mass.

[0005] Most of the reduction in lean mass is due to a loss of skeletal muscle mass, which typically represents 40% of overall body weight and plays a major role in resting energy expenditure, activity, and systemic metabolism. Loss of skeletal muscle during weight loss can cause important functional deficits, and it also significantly reduces energy expenditure, which impairs both weight loss and maintenance of weight loss. Furthermore, after weight loss, many patients eventually regain weight over time, and the weight that is regained is mostly, if not entirely, fat. See Christoffersen et al., “Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss.” Obesity (Silver Spring). Apr 2022;30(4):841-57. Epub 2022 / 03 / 26. This can be especially problematic in older adults, who often have baseline sarcopenia and suffer from age-related impairments in recovery of muscle mass. Thus, there is an increasing focus on the quality of weight loss (reducing fat mass while preserving muscle mass) and maintenance of weight loss (via protection of muscle mass and energy expenditure), as well as increasing recognition that weight loss and maintenance of weight loss may require different therapeutic strategies.

[0006] Thus, a need exists for therapeutics that allow for the preservation of skeletal muscle mass in patients taking GLP-1 receptor agonists. SUMMARY OF THE INVENTION

[0007] Briefly, the present invention addresses the need for therapeutics that allow for the preservation of skeletal muscle mass in patients taking GLP-1 receptor agonists.

[0008] In one aspect, the invention provides a method of improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy,reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength in a patient being treated with a GLP-1 receptor agonist, comprising administering to the patient a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein U is carbon; n is 0 or 1; dashed bond (------) represents a single or double bond; • when the dashed bond (------) represents a single bond, n is 1, and R1aand R1b, together with U, form a methylpiperidine ring of formula:• when the dashed bond (------) represents a double bond, n is 0, and R1ais – CH2CH2CH(CH3)CH2NH2; and R2is H or, wherein represents the point of attachment to the oxygen.

[0009] In another aspect, the invention provides a combination comprising, as active components, a GLP-1 receptor agonist and a compound of formula (I) for separate, sequential or simultaneous administration.

[0010] In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with one or more GLP-1 receptor agonists and one or more acceptable carriers. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Non-limiting embodiments of the invention are described by the drawings presented herein.

[0012] FIG.1 shows that administering Compound B to diet-induced obese mice treated with semaglutide significantly enhanced weight loss.

[0013] FIG.2 shows that administering Compound B to diet-induced obese mice treated with semaglutide significantly decreased fat mass.

[0014] FIG.3 shows that administering Compound B to diet-induced obese mice treated with semaglutide significantly increased strength.

[0015] FIG.4 shows that administering Compound B to diet-induced obese mice treated with semaglutide significantly increased muscle mass.

[0016] FIG.5 shows that administering Compound B to diet-induced obese mice treated with semaglutide significantly increased skeletal muscle fiber size.

[0017] FIG.6 shows that Compound B and semaglutide have synergistic effects towards treatment of obesity in terms of % change in body weight.

[0018] FIGS.7A and 7B show that Compound B and semaglutide have synergistic effects towards treatment of obesity based on initial (7A) and final (7B) body weight.

[0019] FIG.8 shows that Compound B and semaglutide have synergistic effects towards treatment of obesity based on change in body weight.

[0020] FIG.9 shows that Compound B and semaglutide have synergistic effects towards treatment of obesity based on % change in body weight.

[0021] FIG.10 shows that Compound B and semaglutide synergistically decrease adiposity based on change in fat mass.

[0022] FIG.11 shows that Compound B and semaglutide synergistically decrease adiposity based on % change in fat mass.

[0023] FIG.12 shows that Compound B and tirzepatide have synergistic effects towards treatment of obesity based on % change in body weight.

[0024] FIG.13 shows that Compound B and tirzepatide have synergistic effects towards treatment of obesity based on change in body weight.

[0025] FIG.14 shows that Compound B and tirzepatide have synergistic effects towards treatment of obesity based on % change in body weight.

[0026] FIG.15 shows that Compound B and tirzepatide synergistically decrease adiposity based on change in fat mass.

[0027] FIG.16 shows that Compound B and tirzepatide synergistically decrease adiposity based on % change in fat mass. DETAILED DESCRIPTION OF THE INVENTION

[0028] In a first aspect, the invention provides a method of improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy, reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength in a patient being treated with a GLP-1 receptor agonist, comprising administering to the patient a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein U is carbon; n is 0 or 1; dashed bond (------) represents a single or double bond; • when the dashed bond (------) represents a single bond, n is 1, and R1aand R1b, together with U, form a methylpiperidine ring of formula:• when the dashed bond (------) represents a double bond, n is 0, and R1ais – CH2CH2CH(CH3)CH2NH2; and R2is H or, wherein represents the point of attachment to the oxygen.

[0029] GLP-1 receptor agonists promote weight loss primarily by suppressing appetite and food intake (via central nervous system pathways), delaying gastric emptying, and improving insulin sensitivity and glucose control. These effects lead to a caloric deficit and consequently, body weight reduction.

[0030] However, as discussed above, clinical trials and body composition analyses (e.g., using DEXA or MRI) have shown that a substantial proportion of the weight lost with GLP-1 receptor agonists is lean mass (including skeletal muscle), not just fat mass. This reduction is often disproportionate, given that the goal of obesity therapy is preferential fat mass loss. Mechanistic explanations include that: caloric restriction leads to reduced anabolic signaling and negative protein balance; nausea and reduced food intake can cause inadequate protein consumption; and there may be diminished mechanical loading due to less physical activity as body mass decreases.

[0031] There are detrimental clinical consequences associated with the muscle loss that accompanies treatment with GLP-1 receptor agonists. Indeed, loss of lean muscle mass can have serious metabolic and functional implications, including: reduced basal metabolic rate, making long-term weight maintenance harder (predisposing patients to weight regain); reduced strength and physical function, which can be particularly concerning for older adults or patients with comorbidities; impaired glucose regulation, since skeletal muscle is a major site of glucose uptake; and increased frailty and sarcopenia risk, which can worsen morbidity and mortality outcomes.

[0032] Thus, while GLP-1 receptor agonists are effective for weight loss, the quality of weight loss — specifically the fat-to-lean ratio — becomes a critical therapeutic concern.

[0033] Surprisingly, it has been found that administering a compound of formula (I) during the course of treatment with a GLP-1 receptor agonist both enhances total weight reduction, and preserves and / or increases lean muscle mass during the process, thus effectively improving the quality of weight loss while protecting from detrimental clinical consequences otherwise associated with treatment with GLP-1 receptor agonists.

[0034] Combination therapy employing one or more GLP-1 receptor agonists together with a compound of formula (I) or a pharmaceutically acceptable salt thereof allows for patients to maintain lean mass during GLP-1–induced weight loss. Embodiments of the combination therapy thus in turn provide for enhanced metabolic health (e.g., better glucose disposal, higher resting energy expenditure), improved physical function and quality of life, promotion of sustained weight maintenance after cessation of therapy, and a reduced risk of sarcopenia, which is particularly important for aging and chronically ill patient populations.

[0035] It has been found that compounds of formula (I) demonstrate excellent oral bioavailability, pharmacokinetics, and safety in rodent models.

[0036] As used herein, and as would be understood by the person of skill in the art, the recitation of a “compound” - unless expressly further limited - is intended to include salts, solvates and inclusion complexes of that compound as well as any stereoisomeric form, or a mixture of any such forms of that compound in any ratio.

[0037] In methods and embodiments of the invention, the term “subject” refers to the target of administration, e.g. an animal. Thus, the subject of the herein disclosed methods can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. More specifically, the subject of the herein disclosed methods can be a human, a non-human primate, a horse, a dog, a cat, etc. A patient refers to a subject afflicted with, and / or being treated for a disease or disorder. The term “patient” includes human and veterinary subjects. As is understood by those skilled in the art, with regard to a particular method of treatment, a patient is generally considered to be “in need thereof” where a patient would benefit from the claimed treatment — typically someone suffering from, diagnosed with, or at risk of developing the disease or condition that the invention is designed to treat, prevent, or alleviate.

[0038] As used herein, the term “treatment” refers to the management of a subject or the medical management of a patient with the intent to cure, ameliorate, palliate, stabilize, or forestall a disease, pathological condition, or disorder. This term includes palliativetreatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; treatment directed to minimizing or partially or completely inhibiting the development of the associated disease and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease or disorder. Aspects of the invention include the use for aesthetic and self-improvement purposes rather than for curing, ameliorating, or forestalling a disease. For example, such uses include, but are not limited to, the administration of the disclosed compounds in nutraceuticals, medicinal foods, functional foods, energy bars, energy drinks, sports drinks, protein bars, protein powders, tea, coffee, milk, milk products, cereal, oatmeal, infant formulas, supplements (such as multivitamins) or chewing gum.

[0039] As used herein, the terms “administering” and “administration” refer to any method of providing a composition or pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration.

[0040] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disease or disorder being treated and the severity of the disease or disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skills of a person in the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. Ifdesired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications.

[0041] While it may be possible for the compounds of formula (I) to be administered as the raw chemical, when used for treatment methods, it is preferable to present them as a composition, for example, as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more GLP-1 receptor agonists and one or more acceptable carriers. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0042] Embodiments of compositions and formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual) administration. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Embodiments of inventive methods include the step of bringing into association a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient(s) with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0043] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient(s); as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient(s) may also be presented as a bolus, electuary or paste. Embodiments of dosage forms include tablets, capsules and solutions or suspensions. In some embodiments, powders, solutions and / or suspensions are well suited to incorporate the compound of formula (I) into a foodstuff. For example, one might make a drink using water, a solution of the compound described below, and optionally a sugar substitute, salt, and / or small amounts of flavorings and colors.

[0044] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.

[0045] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and / or solutes which render the formulation isotonic with the blood of the intended recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0046] Examples of embodiments of unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of a compound of formula (I), and optionally a GLP-1 receptor agonist. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0047] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. The compounds of formula (I) being basic, salts may be prepared from pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, betulinic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic,salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p-toluenesulfonic, ursolic and the like.

[0048] In some embodiments, dosages for compositions containing a compound of formula (I), perhaps more than some other medicaments, are optimally measured in relation to the body weight of the subject or patient. Dosage levels of 4 mg / kg / day for a 60 kg human would be roughly 250 mg per day. A 4 mg / kg dose might go up to about 750 mg per day for an obese person of about 180 kg.

[0049] In some embodiments, the compound of formula (I) or pharmaceutically acceptable salt thereof is administered to a subject in an amount of about 0.001 to 25 mg / kg / day, based on the weight of the subject (e.g., about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, or 25.0 mg / kg / day). In some embodiments, a dosage level will be about 0.002 to 10 mg / kg / day. In some embodiments, a dosage level will be about 0.004 to 8 mg / kg / day. In some embodiments, a dosage level will be about 2 to 6 mg / kg / day.

[0050] Dosages can be administered in single or multiple doses (e.g., single or multiple doses daily, weekly, etc.).

[0051] In some embodiments, the compositions are in a dosage form of, e.g., 25 to 750 milligrams of a compound of formula (I) (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, or 750 mg).

[0052] In some embodiments, the invention provides compositions for oral administration, e.g., in the form of a solution, suspension, or in tablets containing, e.g., 25 to 750 milligrams of a compound of formula (I).

[0053] The term “optically pure” as used in describing compounds herein means that the compositions contain at least 90% by weight of one enantiomer and 10% by weight or less of any other. In a more preferred embodiment, the term "substantially optically pure" means that the composition contains at least 99% by weight of one enantiomer, and 1% or less of other(s).

[0054] In some embodiments, the compound of the invention is optically pure.

[0055] In some embodiments, the compound of the invention is substantially optically pure.

[0056] In some embodiments of formula (I), n is 0 (i.e., R1bis not present). In some embodiments, n is 1.

[0057] In some embodiments, the methylpiperidine ring,.

[0058] In some embodiments, R2is H.

[0059] In some embodiments, R2is: ,

[0060] In some embodiments, the compound of formula (I) is a compound of one of the following formulas (I’), (Ia), (Ia’), (Ib) (tomatidine), or (Ic) (α-tomatine):,or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the compound of formula (I) (e.g., the compound of formula (I’), (Ia), (Ia’), (Ib), or (Ic)), is in the form of a pharmaceutically acceptable salt.

[0062] Compounds of formula (I) may be present in any pharmaceutically acceptable salt. In some embodiments, the salt is a hydrochloride or mesylate salt.

[0063] In some embodiments, the compound of formula (I) is administered as a salt having formula (Iaa):wherein X- is a pharmaceutically acceptable anion, e.g., Cl- or CH3SO3-.

[0064] In some embodiments, the compound of formula (I) is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the compound of formula (I) is a mesylate or hydrochloride salt of a compound of formula (Ia).

[0065] In some embodiments, the compound of formula (I) is a compound of formula (Ia’) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the compound of formula (I) is a mesylate or hydrochloride salt of a compound of formula (Ia’).

[0066] In some embodiments, the compound of formula (I) is a compound of formula (Ib) (tomatidine) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the compound of formula (I) is a mesylate or hydrochloride salt of a compound of formula (Ib).

[0067] In some embodiments, the compound of formula (I) is a compound of formula (Ic) (α-tomatine) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the compound of formula (I) is a mesylate or hydrochloride salt of a compound of formula (Ic).

[0068] In some embodiments, the inventive method is a method for improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy, reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength in a patient being treated with a GLP-1 receptor agonist.

[0069] In some embodiments, the inventive method provides for improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy, reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength in a patient being treated with a GLP-1 receptor agonist as compared to results achievable with treatment of the GLP-1 receptor agonist alone.

[0070] As used herein, improving weight loss means achieving a statistically significant increase in the amount or percentage of body weight reduced, or achieving a more favorable composition of weight loss (e.g., greater fat mass reduction or preservation of lean mass). In some embodiments, administration of a compound of formula (I) in a patient being treated with a GLP-1 receptor agonist results in improved weight loss as compared to treatment with the GLP-1 receptor agonist alone. In some embodiments, improving weight loss comprises reducing body fat mass, reducing central adiposity, and / or increasing rate of weight reduction. Improving weight loss can result in lowering the body mass index (BMI) of a patient.

[0071] In some embodiments, the invention provides a method for reducing body fat mass in a patient.

[0072] In some embodiments, the invention provides a method for reducing central adiposity in a patient.

[0073] In some embodiments, the invention provides a method for reducing muscle loss in a patient (e.g., reducing the amount of muscle that would be lost during treatment with a GLP-1 receptor agonist alone). In some embodiments, reducing muscle loss comprises maintaining muscle mass in a patient.

[0074] In some embodiments, the invention provides a method for maintaining muscle mass in a patient.

[0075] In some embodiments, the invention provides a method for increasing muscle mass in a patient.

[0076] In some embodiments, the invention provides a method for reducing weakness, reducing fatigue, improving glycemic control, improving endurance exercise capacity, improving skeletal muscle mitochondrial function, improving energy expenditure, improving muscle quality, improving muscle specific force, improving glucose control, increasing lean body mass, treating obesity, or treating diabetes (type 1 and / or type 2) in a patient. In some embodiments, the invention provides any one or more of these methods in addition to a method for improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy, reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength.

[0077] In some embodiments, the invention provides a method for use within a treatment regimen for treating diabetes, obesity, dyslipidemia, or metabolic syndrome.

[0078] In some embodiments, the invention provides a method for treating a patient that has been diagnosed with diabetes, obesity, dyslipidemia, or metabolic syndrome.

[0079] In some embodiments of the inventive method, the patient is obese or overweight.

[0080] In some embodiments, the inventive method comprises treating a subject with a compound of formula (I) to alleviate or reduce complications associated with obesity. In some embodiments, the compounds of formula (I) are particularly useful for treating patients suffering from complications associated with obesity (including but not limited to nonalcoholic fatty liver disease (NAFLD), insulin resistance, dyslipidemia, cardiovascular disorders, and musculoskeletal impairments). When administered in combination with a GLP-1 receptor agonist, the compounds of formula (I) enhance the therapeutic benefits of weight reduction while mitigating adverse metabolic and tissue-related consequences often observed with monotherapy. This combination therapy offers synergistic effects that improve systemic metabolic health, support organ function, and reduce the progression of obesity- related comorbidities. Accordingly, the compounds of formula (I) provide a valuable therapeutic approach for managing peripheral diseases and disorders linked to obesity and metabolic dysfunction.

[0081] In some embodiments, the invention provides a method as disclosed herein (e.g., a method of improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy, reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength) comprising administering (separately, simultaneously, or sequentially) to a subject a compound of formula (I) and a GLP-1 receptor agonist.

[0082] In some embodiments, the inventive method comprises use of a compound of formula (I) for treating a subject that is being treated with a GLP-1 receptor agonist for addiction or substance abuse (e.g., alcohol addiction, drug addiction, etc.). Indeed, in addition to enhancing the weight loss effects of GLP-1 receptor agonists while preserving lean mass, compounds of formula (I) may also offer significant benefits for patients using GLP-1 therapies for addiction management. GLP-1 receptor agonists have been shown to modulate reward pathways in the brain, reducing craving and compulsive behaviors associated with substance use disorders. By improving the pharmacodynamic profile of GLP-1 receptor agonists, compounds of formula (I) could amplify these neuromodulatory effects, leading to greater reductions in addictive behaviors and relapse rates. Furthermore, by promoting healthier body composition and metabolic stability, the compounds of formula (I) may enhance overall well-being and treatment adherence, thereby supporting more sustainable recovery outcomes in patients undergoing GLP-1–based addiction therapy.

[0083] In some embodiments, the invention provides a method of improving the safety and efficacy of a GLP-1 receptor agonist by administering with the GLP-1 receptor agonist a compound of formula (I).

[0084] In some embodiments of the invention, the GLP-1 receptor agonist is a single GLP-1 receptor agonist, dual GLP-1 / GIP receptor agonist, dual GLP-1 receptor agonist / GIP receptor antagonist, triple GLP-1 / GIP / glucagon receptor agonist, or dual GLP-1 receptor agonist / amylin receptor agonist.

[0085] In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of exenatide, dulaglutide, liraglutide, lixisenatide, semaglutide, tirzepatide, cotadutide, noiiglutide, oxyntomodulin, mazdutide, retatrutide, HM15211, UBT251, albiglutide, beinaglutide, PEG-loxenatide, pemvidutide, danuglipron, efpeglenatide, orforglipron, survodutide, maridebart, VK2735, CT-388, CT-996, CT-868, TERN-601, GSBR-1290, CagriSema, and amycretin.

[0086] In some embodiments, the GLP-1 receptor agonist is semaglutide.

[0087] In some embodiments, the GLP-1 receptor agonist is tirzepatide.

[0088] In another aspect the invention provides a compound of formula (I) for use according to any one or more methods described herein.

[0089] In some embodiments, the invention provides a compound of formula (I) for use in improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy, reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength in a patient being treated with a GLP-1 receptor agonist.

[0090] In some embodiments, the invention provides use of a compound of formula (I) in the manufacture of a medicament for the methods disclosed herein, e.g., for improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy, reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength in a patient being treated with a GLP-1 receptor agonist.

[0091] In another aspect, the invention provides a combination comprising, as active components, a GLP-1 receptor agonist and a compound of formula (I) for separate, sequential or simultaneous administration.

[0092] In some embodiments of the inventive combination, the compound of formula (I) and the GLP-1 receptor agonist are for administration in separate dosage forms.

[0093] In some embodiments of the inventive combination, the compound of formula (I) and the GLP-1 receptor agonist are for administration in simultaneous dosage forms.

[0094] In some embodiments of the inventive combination, the compound of formula (I) and the GLP-1 receptor agonist are for administration in sequential dosage forms

[0095] In some embodiments, the compound of formula (I) and the GLP-1 receptor agonist are formulated together.

[0096] In some embodiments, the compound of formula (I) and the GLP-1 receptor agonist are formulated separately.

[0097] In some embodiments, the compound of formula (I) and the GLP-1 receptor agonist are separately formulated as two or more different preparations, and the preparation containing the compound of formula (I) and the preparation containing the GLP-1 receptor agonist can be administered simultaneously, separately, or sequentially. The dosing interval for the separate administration is not particularly limited and can be selected so as to optimally exert the respective effects of the compound of formula (I) and the GLP-1 receptor agonist, and the effect of concomitant use. For sequential administration, the preparation containing the compound of formula (I) and the preparation containing the GLP-1 receptor agonist can be administered in any order

[0098] In some embodiments of the inventive method, at 6 months following combination treatment with administration of the compound of formula (I) and GLP-1 receptor agonist, a subject exhibits one or more parameter change selected from the following, relative to the subject at commencement of the combination treatment: • less than 10% loss (e.g. less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% loss) of lean mass; • less than 10% loss (e.g. less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% loss) of skeletal muscle mass; • less than 10% loss (e.g. less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% loss) of skeletal muscle fiber size; • less than 10% loss (e.g. less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% loss) of strength.

[0099] In some embodiments of the inventive method, at 12 months following combination treatment with administration of the compound of formula (I) and GLP-1 receptor agonist, a subject exhibits one or more parameter change selected from the following, relative to the subject at commencement of the combination treatment:• less than 10% loss (e.g. less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% loss) of lean mass; • less than 10% loss (e.g. less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% loss) of skeletal muscle mass; • less than 10% loss (e.g. less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% loss) of skeletal muscle fiber size; • less than 10% loss (e.g. less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% loss) of strength.

[0100] In some embodiments of the inventive method, at 6 months following combination treatment with administration of the compound of formula (I) and GLP-1 receptor agonist, a subject exhibits one or more parameter change selected from the following, relative to the subject at commencement of the combination treatment: • at least 0.5% increase (e.g. at least 0.5%, 1%, 2%, 3%, 4%, or 5% increase) in lean mass; • at least 0.5% increase (e.g. at least 0.5%, 1%, 2%, 3%, 4%, or 5% increase) in skeletal muscle mass; • at least 0.5% increase (e.g. at least 0.5%, 1%, 2%, 3%, 4%, or 5% increase) in skeletal muscle fiber size; • at least 0.5% increase (e.g. at least 0.5%, 1%, 2%, 3%, 4%, or 5% increase) in strength.

[0101] In some embodiments of the inventive method, at 12 months following combination treatment with administration of the compound of formula (I) and GLP-1 receptor agonist, a subject exhibits one or more parameter change selected from the following, relative to the subject at commencement of the combination treatment: • at least 0.5% increase (e.g. at least 0.5%, 1%, 2%, 3%, 4%, or 5% increase) in lean mass; • at least 0.5% increase (e.g. at least 0.5%, 1%, 2%, 3%, 4%, or 5% increase) in skeletal muscle mass; • at least 0.5% increase (e.g. at least 0.5%, 1%, 2%, 3%, 4%, or 5% increase) in skeletal muscle fiber size;• at least 0.5% increase (e.g. at least 0.5%, 1%, 2%, 3%, 4%, or 5% increase) in strength.

[0102] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, and / or methods claimed herein are made and evaluated. They are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

[0103] Certain materials, reagents and kits were obtained from specific vendors as indicated below, and as appropriate the vendor catalog, part or other number specifying the item are indicated. “Sigma” is Sigma-Aldrich Corporation, Saint Louis, Missouri, USA. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0104] Compounds of formula (Ia) and (Ia’) can be synthesized, for example, as described in United States Patent Nos.10,662,219 and 11,136,348, the contents of which are hereby incorporated by reference herein. These patents also describe the utility of furostanol compounds for treating muscle atrophy and as muscle hypertrophic agents. Compounds of formula (Ib) and (Ic) are commercially available, and are described, for example, in International Patent Application Publications WO / 2012 / 170546 and WO / 2014 / 022772, the contents of which are hereby incorporated by reference herein. WO / 2025 / 090589, which is also incorporated by reference herein, discloses certain furostan-3-ol derivatives for the treatment of obesity and diabetes as alternatives to GLP-1 receptor agonists, or as therapeutics for after completion of treatment therewith, but combination therapy (or its surprising ability to overcome deleterious side effects of GLP-1 receptor agonist therapies) is not contemplated.

[0105] A compound of formula (Ia’) may be synthesized as follows:

[0106] Compound A. Tert-Butyl ((S)-4-((2aS,4S,6aS,6bS,8aS,8bS,11aS,12aS,12bR)-4- hydroxy-6a,8a,9-trimethyl-2,2a,3,4,5,6,6a,6b,7,8,8a,8b,11a,12,12a,12b-hexadecahydro-1H- naphtho[2',1':4,5]indeno[2,1-b]furan-10-yl)-2-methylbutyl)carbamate

[0107] A solution of tomatidine hydrochloride (250 mg, 0.55 mmol), di-tert-butyl dicarbonate (152 µL, 0.66 mmol), potassium carbonate (182 mg, 1.32 mmol) in 1 mL of 1,4- dioxane is stirred at 50 °C for 18 h. The solution is diluted with water and extracted with 3 times with ether; the combined extracts are washed with water, brine, dried over anhyd. MgSO4, concentrated in vacuo, and the residue is purified by flash chromatography eluting with hexanes and ethyl acetate to afford 215 mg of the title compound as a white solid, 76%.1H NMR (400 MHz, CDCl3) and13C NMR (100 MHz, CDCl3) are consistent. LC tr=7.8 min (C-18 column, 5 to 95% acetonitrile / water over 6 min at 1.7 mL / min with detection 210 nm, at 23oC). ES(pos)MS m / z 516 (M+H calcd for C32H54NO4 requires 516).

[0108] Compound B. – HCl salt of the compound of formula (Ia’). (2aS,4S,6aS,6bS,8aS,8bS,11aS,12aS,12bR)-10-((S)-4-Amino-3-methylbutyl)-6a,8a,9- trimethyl-2,2a,3,4,5,6,6a,6b,7,8,8a,8b,11a,12,12a,12b-hexadecahydro-1H- naphtho[2',1':4,5]indeno[2,1-b]furan-4-ol hydrochloride

[0109] A solution of tert-butyl ((S)-4-((2aS,4S,6aS,6bS,8aS,8bS,11aS,12aS,12bR)-4- hydroxy-6a,8a,9-trimethyl-2,2a,3,4,5,6,6a,6b,7,8,8a,8b,11a,12,12a,12b-hexadecahydro-1H- naphtho[2',1':4,5]indeno[2,1-b]furan-10-yl)-2-methylbutyl)carbamate (50 mg, 0.10 mmol) and 1 mL of 4M HCl in 1,4-dioxane for 0.5 h. The solution is concentrated and the residue dissolved in acetonitrile whereupon a precipitate is formed that is isolated by filtration and dried in vacuo to afford 33.7 mg of pure product 75%.1H NMR (400 MHz, CDCl3) and13CNMR (100 MHz, CD3OD) consistent. LC tr=3.7 min (C-18 column, 5 to 95% acetonitrile / water over 6 min at 1.7 mL / min with detection 210 nm, at 23oC). ES(pos)MS m / z 416 (M+H calcd for C27H46NO2requires 416).

[0110] Compound C. Preparation of (((S)-4-((2aS,4S,6aS,6bR,8aS,8bS,11aS,12aS,12bR)- 4-hydroxy-6a,8a,9,12b-tetramethyl-2,2a,3,4,5,6,6a,6b,7,8,8a,8b,11a,12,12a,12b- hexadecahydro-1H-naphtho[2',1':4,5]indeno[2,1-b]furan-10-yl)-2- methylbutyl)ammonio)methanesulfonate.

[0111] Compound A, tert-Butyl ((S)-4-((2aS,4S,6aS,6bS,8aS,8bS,11aS,12aS,12bR)-4- hydroxy-6a,8a,9-trimethyl-2,2a,3,4,5,6,6a,6b,7,8,8a,8b,11a,12,12a,12b-hexadecahydro-1H- naphtho[2',1':4,5]indeno[2,1-b]furan-10-yl)-2-methylbutyl)carbamate, (250 mg, 0.47 mmol), is dissolved in 1,4-dioxane and is treated with methane sulfonic acid, (2 equiv). After stirring at room temperature for 1 h the mixture is concentrated in vácuo and the residue is dissolved in acetonitrile whereupon a precipitate is formed that was isolated by filtration and dried in vacuo to afford 210.7 mg of pure product 86%.1H NMR (400 MHz, CDCl3) and13C NMR (100 MHz, CDCl3) is consistent with the desired product. ES (pos) MS m / z 523 (M+H calcd for C29H49NO5S requires 523).

[0112] The following examples describe non-limiting embodiments of combination testing involving GLP-1 receptor agonists and a compound of formula (I).

[0113] Example 1. In diet-induced obese mice treated with semaglutide, Compound B significantly enhances weight loss and significantly decreases fat mass, while also significantly increasing strength and skeletal muscle mass.

[0114] Weight-matched cohorts of 11-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD; 55% calories from fat) for 9 weeks to induce obesity.

[0115] Obese mice were then administered daily subcutaneous injections of the GLP-1 receptor agonist semaglutide (120 µg / kg / day for 14 days) while also receiving ad libitum access to either HFD or HFD supplemented with 0.05% Compound B for 14 days.

[0116] To determine the effect of Compound B on weight loss in semaglutide-treated mice, obese mice were weighed before and after the 14-day treatment with semaglutide in the absence and presence of Compound B, and then the percent change in body weight was calculated.

[0117] To determine the effect of Compound B on fat mass, mice were euthanized after the 14-day treatment with semaglutide in the absence and presence of Compound B, and then bilateral retroperitoneal fat pads were dissected, combined, and weighed.

[0118] To determine the effect of Compound B on strength in semaglutide-treated mice, in vivo grip strength was assessed after 13 days of treatment with semaglutide in the absence and presence of Compound B.

[0119] To determine the effect of Compound B on skeletal muscle mass in semaglutide- treated mice, mice were euthanized after the 14-day treatment with semaglutide in the absence and presence of Compound B, and then bilateral gastrocnemius skeletal muscles were dissected, combined and weighed.

[0120] Results are shown in Table 1. Data are means ± SEM from 7-8 mice per cohort. *P < 0.05. ***P < 0.001. ****P < 0.0001. Table 1

[0121] Example 2. In diet-induced obese mice treated with semaglutide, Compound B significantly enhances weight loss.

[0122] Weight-matched cohorts of 11-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD; 55% calories from fat) for 9 weeks to induce obesity.

[0123] Obese mice were then administered daily subcutaneous injections of semaglutide (120 µg / kg / day for 14 days) while also receiving ad libitum access to either HFD or HFD supplemented with 0.05% Compound B for 14 days.

[0124] To determine the effect of Compound B on weight loss in semaglutide-treated mice, obese mice were weighed before and after the 14-day treatment with semaglutide in the absence and presence of Compound B, and then the percent change in body weight was calculated.

[0125] Results are shown in FIG.1. Data are means ± SEM from 7-8 mice per cohort. ***P < 0.001.

[0126] Example 3. In diet-induced obese mice treated with semaglutide, Compound B significantly decreases fat mass.

[0127] Weight-matched cohorts of 11-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD; 55% calories from fat) for 9 weeks to induce obesity.

[0128] Obese mice were then administered daily subcutaneous injections of semaglutide (120 µg / kg / day for 14 days) while also receiving ad libitum access to either HFD or HFD supplemented with 0.05% Compound B for 14 days.

[0129] To determine the effect of Compound B on fat mass, mice were euthanized after the 14-day treatment with semaglutide in the absence and presence of Compound B, and then bilateral retroperitoneal fat pads were dissected, combined, and weighed.

[0130] Results are shown in FIG.2. Data are means ± SEM from 7-8 mice per cohort. *P < 0.05.

[0131] Example 4. In diet-induced obese mice treated with semaglutide, Compound B significantly increases strength.

[0132] Weight-matched cohorts of 11-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD; 55% calories from fat) for 9 weeks to induce obesity.

[0133] Obese mice were then administered daily subcutaneous injections of semaglutide (120 µg / kg / day for 14 days) while also receiving ad libitum access to either HFD or HFD supplemented with 0.05% Compound B for 14 days.

[0134] To determine the effect of Compound B on strength in semaglutide-treated mice, in vivo grip strength was assessed after 13 days of treatment with semaglutide in the absence and presence of Compound B.

[0135] Results are shown in FIG.3. Data are means ± SEM from 7-8 mice per cohort. ****P < 0.0001.

[0136] Example 5. In diet-induced obese mice treated with semaglutide, Compound B significantly increases skeletal muscle mass.

[0137] Weight-matched cohorts of 11-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD; 55% calories from fat) for 9 weeks to induce obesity.

[0138] Obese mice were then administered daily subcutaneous injections of semaglutide (120 µg / kg / day for 14 days) while also receiving ad libitum access to either HFD or HFD supplemented with 0.05% Compound B for 14 days.

[0139] To determine the effect of Compound B on skeletal muscle mass in semaglutide- treated mice, mice were euthanized after the 14-day treatment with semaglutide in the absence and presence of Compound B, and then bilateral gastrocnemius skeletal muscles were dissected, combined, and weighed.

[0140] Results are shown in FIG.4. Data are means ± SEM from 7 mice per cohort. *P < 0.05.

[0141] Example 6. In diet-induced obese mice treated with semaglutide, Compound B significantly increases skeletal muscle fiber size.

[0142] Weight-matched cohorts of 11-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD; 55% calories from fat) for 9 weeks to induce obesity. Obese mice were then administered daily subcutaneous injections of semaglutide (120 µg / kg / day for 14 days) while also receiving ad libitum access to either HFD or HFD supplemented with 0.05% Compound B for 14 days.

[0143] To determine the effect of Compound B on skeletal muscle fiber size in semaglutide-treated mice, mice were euthanized after the 14-day treatment with semaglutide in the absence and presence of Compound B, and then tibialis anterior skeletal muscles were dissected, immediately placed in optimal cutting temperature (O.C.T.) compound (Tissue- Tek, catalog no.4583), and snap frozen using a Stand-Alone Gentle Jane from Instrumedics Inc. Cryosections (10 µm) were taken from muscle mid-bellies using a Cryostar HM525 NX (Epredia), immersed in acetone for 10 min at -20 °C, rinsed three times with phosphate- buffered saline (PBS; Gibco), blocked in Buffer A (PBS, pH 7.4, 0.5% Triton X-100, and 5% horse serum) for 20 min at 21 °C, rinsed three times with PBS, incubated for 1 h at 21 °C in Buffer A supplemented with a 1:250 dilution of rabbit polyclonal anti-laminin IgG (Sigma, catalog no. L9393), rinsed three times with PBS, incubated for 1 h at 21 °C in Buffer A supplemented with a 1:500 dilution of Alexa Fluor 568-conjugated anti-rabbit-IgG (Invitrogen, catalog no.11011), rinsed three times with PBS, and then mounted in ProLongGold Antifade reagent (Invitrogen, catalog no. P36930) and overlayed with a coverslip (FisherScientific, catalog no.12-545k). Histological sections were imaged on a Nikon Eclipse Ti2-U inverted microscope equipped with Nikon Elements Ar software package and fluorescence microscopy filter cubes from IDEX Health and Science (Rochester, NY). Image analysis was performed using the Nikon Elements General Analysis (GA3) software using the homogenous area function.

[0144] Results are shown in FIG.5. Data are mean cross-sectional areas ± SEM of > 11,000 skeletal muscle fibers per condition. ****P < 0.0001.

[0145] Example 7. Compound B and semaglutide synergistically treat obesity and decrease adiposity.

[0146] Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet-induced obese mice were divided into four weight-matched groups.

[0147] Group 1 (“No Drug”) received ad libitum access to HFD for 14 days.

[0148] Group 2 (“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days.

[0149] Group 3 (“Semaglutide”) received ad libitum access to HFD plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days.

[0150] Group 4 (“Compound B + Semaglutide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days.

[0151] Mice were weighed on day 0 (initial body weight) and on day 14 (final body weight), and then absolute and relative changes in body weight between days 0 and 14 were calculated.

[0152] Mice were subjected to NMR analysis of fat mass on day 0 (initial fat mass) and on day 14 (final fat mass), and then absolute and relative changes in fat mass between days 0 and 14 were calculated.

[0153] Results are shown in Table 2. Data are means ± SEM from 8-10 mice per cohort.Table 2

[0154] Testing results are shown in FIGS.6 – 11.

[0155] FIG.6: Compound B and semaglutide have synergistic effects towards treatment of obesity in terms of % change in body weight. Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet-induced obese mice were divided into four weight-matched groups. Group 1 (“No Drug”) received ad libitum access to HFD for 14 days. Group 2 (“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days. Group 3 (“Semaglutide”) received ad libitum access to HFD plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days. Group 4 (“Compound B + Semaglutide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days. Mice were weighed every day, and the percent change in body weight relative to day 0 was calculated. Data are means ± SEM from 8-10 mice per cohort.

[0156] FIGS.7A and 7B: Compound B and semaglutide have synergistic effects towards treatment of obesity based on initial and final body weight. Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet-induced obese mice were divided into four weight-matched groups. Group 1 (“No Drug”) received ad libitum access to HFD for 14 days. Group 2 (“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days. Group 3 (“Semaglutide”) received ad libitum access to HFD plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days. Group 4 (“Compound B +Semaglutide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days. The graphs show initial body weights (day 0) and final body weights (day 14). Data are means ± SEM from 8-10 mice per cohort. P-values were determined by one-way ANOVA with Tukey’s multiple comparisons test. “n.s.” denotes P > 0.05. *P < 0.05. ***P < 0.001. ****P < 0.0001.

[0157] FIG.8: Compound B and semaglutide have synergistic effects towards treatment of obesity based on change in body weight. Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet-induced obese mice were divided into four weight-matched groups. Group 1 (“No Drug”) received ad libitum access to HFD for 14 days. Group 2 (“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days. Group 3 (“Semaglutide”) received ad libitum access to HFD plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days. Group 4 (“Compound B + Semaglutide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days. Mice were weighed on days 0 and 14, and then absolute changes in body weight between days 0 and 14 were calculated. Data are means ± SEM from 8-10 mice per cohort. P-values were determined by one-way ANOVA with Tukey’s multiple comparisons test. “n.s.” denotes P > 0.05. *P < 0.05. **P < 0.01. ****P < 0.0001.

[0158] FIG.9: Compound B and semaglutide have synergistic effects towards treatment of obesity based on % change in body weight. Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet-induced obese mice were divided into four weight-matched groups. Group 1 (“No Drug”) received ad libitum access to HFD for 14 days. Group 2 (“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days. Group 3 (“Semaglutide”) received ad libitum access to HFD plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days. Group 4 (“Compound B + Semaglutide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days. Mice were weighed on days 0 and 14, and then percent changes in body weight between days 0 and 14 were calculated. Data are means ± SEM from 8-10 mice per cohort. P-values were determined by one-way ANOVA with Tukey’s multiple comparisons test. “n.s.” denotes P > 0.05. **P < 0.01. ***P < 0.001. ****P < 0.0001.

[0159] FIG.10: Compound B and semaglutide synergistically decrease adiposity based on change in fat mass. Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet-induced obese mice were divided into four weight-matched groups. Group 1 (“No Drug”) received ad libitum access to HFD for 14 days. Group 2 (“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days. Group 3 (“Semaglutide”) received ad libitum access to HFD plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days. Group 4 (“Compound B + Semaglutide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days. Mice were subjected NMR analysis of fat mass on days 0 and 14, and then absolute changes in fat mass between days 0 and 14 were calculated. Data are means ± SEM from 8-10 mice per cohort. P-values were determined by one-way ANOVA with Tukey’s multiple comparisons test. “n.s.” denotes P > 0.05. *P < 0.05. **P < 0.01. ****P < 0.0001.

[0160] FIG.11: Compound B and semaglutide synergistically decrease adiposity based on % change in fat mass. Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet- induced obese mice were divided into four weight-matched groups. Group 1 (“No Drug”) received ad libitum access to HFD for 14 days. Group 2 (“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days. Group 3 (“Semaglutide”) received ad libitum access to HFD plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days. Group 4 (“Compound B + Semaglutide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of semaglutide (12 µg / kg / day) for 14 days. Mice were subjected NMR analysis of fat mass on days 0 and 14, and then relative changes in fat mass between days 0 and 14 were calculated. Data are means ± SEM from 8-10 mice per cohort. P-values were determined by one-way ANOVA with Tukey’s multiple comparisons test. “n.s.” denotes P > 0.05. ****P < 0.0001.

[0161] Example 8. Compound B and tirzepatide synergistically treat obesity and decrease adiposity.

[0162] Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet-induced obese mice were divided into four weight-matched groups.

[0163] Group 1 (“No Drug”) received ad libitum access to HFD for 14 days.

[0164] Group 2 (“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days.

[0165] Group 3 (“Tirzepatide”) received ad libitum access to HFD plus daily subcutaneous injections of tirzepatide for 14 days (5 µg / kg / day for the first 7 days, and then 10 µg / kg / day for the next 7 days).

[0166] Group 4 (“Compound B + Tirzepatide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of tirzepatide for 14 days (5 µg / kg / day for the first 7 days, and then 10 µg / kg / day for the next 7 days).

[0167] Mice were weighed on day 0 (initial body weight) and on day 14 (final body weight), and then absolute and relative changes in body weight between days 0 and 14 were calculated.

[0168] Mice were subjected NMR analysis of fat mass on day 0 (initial fat mass) and on day 14 (final fat mass), and then absolute and relative changes in fat mass between days 0 and 14 were calculated.

[0169] Results are shown in Table 3. Data are means ± SEM from 8-10 mice per cohort. Table 3

[0170] Testing results are shown in FIGS.12 – 16.

[0171] FIG.12: Compound B and tirzepatide have synergistic effects towards treatment of obesity based on % change in body weight. Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet-induced obese mice were divided into four weight-matched groups. Group 1 (“No Drug”) received ad libitum access to HFD for 14 days. Group 2(“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days. Group 3 (“Tirzepatide”) received ad libitum access to HFD plus daily subcutaneous injections of tirzepatide for 14 days (5 µg / kg / day for the first 7 days, and then 10 µg / kg / day for the next 7 days). Group 4 (“Compound B + Tirzepatide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of tirzepatide for 14 days (5 µg / kg / day for the first 7 days, and then 10 µg / kg / day for the next 7 days). Mice were weighed every day, and the percent change in body weight relative to day 0 was calculated. Data are means ± SEM from 8-10 mice per cohort.

[0172] FIG.13: Compound B and tirzepatide have synergistic effects towards treatment of obesity based on change in body weight. Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet-induced obese mice were divided into four weight-matched groups. Group 1 (“No Drug”) received ad libitum access to HFD for 14 days. Group 2 (“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days. Group 3 (“Tirzepatide”) received ad libitum access to HFD plus daily subcutaneous injections of tirzepatide for 14 days (5 µg / kg / day for the first 7 days, and then 10 µg / kg / day for the next 7 days). Group 4 (“Compound B + Tirzepatide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of tirzepatide for 14 days (5 µg / kg / day for the first 7 days, and then 10 µg / kg / day for the next 7 days). Mice were weighed on days 0 and 14, and then absolute changes in body weight between days 0 and 14 were calculated. Data are means ± SEM from 8-10 mice per cohort. P-values were determined by one-way ANOVA with Tukey’s multiple comparisons test. “n.s.” denotes P > 0.05. *P < 0.05. **P < 0.01. ****P < 0.0001.

[0173] FIG.14: Compound B and tirzepatide have synergistic effects towards treatment of obesity based on % change in body weight. Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet-induced obese mice were divided into four weight-matched groups. Group 1 (“No Drug”) received ad libitum access to HFD for 14 days. Group 2 (“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days. Group 3 (“Tirzepatide”) received ad libitum access to HFD plus daily subcutaneous injections of tirzepatide for 14 days (5 µg / kg / day for the first 7 days, and then 10 µg / kg / day for the next 7 days). Group 4 (“Compound B + Tirzepatide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of tirzepatide for 14 days (5 µg / kg / day for the first 7 days, and then 10 µg / kg / day for the next 7 days). Mice wereweighed on days 0 and 14, and then percent changes in body weight between days 0 and 14 were calculated. Data are means ± SEM from 8-10 mice per cohort. P-values were determined by one-way ANOVA with Tukey’s multiple comparisons test. “n.s.” denotes P > 0.05. **P < 0.01.0.0001.

[0174] FIG.15: Compound B and tirzepatide synergistically decrease adiposity based on change in fat mass. Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet-induced obese mice were divided into four weight-matched groups. Group 1 (“No Drug”) received ad libitum access to HFD for 14 days. Group 2 (“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days. Group 3 (“Tirzepatide”) received ad libitum access to HFD plus daily subcutaneous injections of tirzepatide for 14 days (5 µg / kg / day for the first 7 days, and then 10 µg / kg / day for the next 7 days). Group 4 (“Compound B + Tirzepatide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of tirzepatide for 14 days (5 µg / kg / day for the first 7 days, and then 10 µg / kg / day for the next 7 days). Mice were subjected NMR analysis of fat mass on days 0 and 14, and then absolute changes in fat mass between days 0 and 14 were calculated. Data are means ± SEM from 8-10 mice per cohort. P-values were determined by one-way ANOVA with Tukey’s multiple comparisons test. “n.s.” denotes P > 0.05. *P < 0.05. **P < 0.01. ****P < 0.0001.

[0175] FIG.16: Compound B and tirzepatide synergistically decrease adiposity based on % change in fat mass. Six-week-old male C57BL / 6 mice were provided ad libitum access to high-fat diet (HFD) for 14 weeks to induce obesity. At 20 weeks of age (day 0), diet-induced obese mice were divided into four weight-matched groups. Group 1 (“No Drug”) received ad libitum access to HFD for 14 days. Group 2 (“Compound B”) received ad libitum access to HFD containing 0.05% Compound B for 14 days. Group 3 (“Tirzepatide”) received ad libitum access to HFD plus daily subcutaneous injections of tirzepatide for 14 days (5 µg / kg / day for the first 7 days, and then 10 µg / kg / day for the next 7 days). Group 4 (“Compound B + Tirzepatide”) received ad libitum access to HFD containing 0.05% Compound B plus daily subcutaneous injections of tirzepatide for 14 days (5 µg / kg / day for the first 7 days, and then 10 µg / kg / day for the next 7 days). Mice were subjected NMR analysis of fat mass on days 0 and 14, and then relative changes in fat mass between days 0 and 14 were calculated. Data are means ± SEM from 8-10 mice per cohort. P-values were determined by one-way ANOVA with Tukey’s multiple comparisons test. “n.s.” denotes P > 0.05. *P < 0.05. **P < 0.01.

Claims

CLAIMS 1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein U is carbon; n is 0 or 1; dashed bond (------) represents a single or double bond; • when the dashed bond (------) represents a single bond, n is 1, and R1aand R1b, together with U, form a methylpiperidine ring of formula:• when the dashed bond (------) represents a double bond, n is 0, and R1ais – CH2CH2CH(CH3)CH2NH2; and R2is H or, wherein represents the point of attachment to the oxygen, for use in improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy, reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength in a patient being treated with a GLP-1 receptor agonist.

2. The compound for use according to claim 1, wherein the compound of formula (I) is a compound of formula (I’):

3. The compound for use according to claim 1, wherein the compound of formula (I) is a compound of formula (Ia):

4. The compound for use according to claim 3, wherein the compound of formula (Ia) is a compound of formula (Ia’):(Ia’).

5. The compound for use according to claim 1, wherein the compound of formula (I) is a compound of formula (Ib):(Ib).

6. The compound for use according to claim 1, wherein the compound of formula (I) is a compound of formula (Ic):

7. The compound for use according to any one of the preceding claims, wherein the compound of formula (I) is in the form of a pharmaceutically acceptable salt.

8. The compound for use according to any one of the preceding claims, wherein the compound of formula (I) is in the form of a mesylate salt.

9. The compound for use according to claim 1, wherein the compound of formula (I) is a compound of formula (Iaa):wherein X- is a pharmaceutically acceptable anion, e.g., Cl- or CH3SO3-.

10. A method of improving weight loss, reducing body weight, reducing body fat mass, reducing muscle loss, reducing muscle atrophy, reducing muscle weakness, increasing muscle mass, and / or increasing muscle strength in a patient being treated with a GLP-1 receptor agonist, comprising administering to the patient a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein U is carbon; n is 0 or 1; dashed bond (------) represents a single or double bond; • when the dashed bond (------) represents a single bond, n is 1, and R1aand R1b, together with U, form a methylpiperidine ring of formula:• when the dashed bond (------) represents a double bond, n is 0, and R1ais – CH2CH2CH(CH3)CH2NH2; and R2is H or, wherein represents the point of attachment to the oxygen.

11. The method according to claim 10, wherein the compound of formula (I) is a compound of formula (I’):

12. The method according to claim 10, wherein the compound of formula (I) is a compound of formula (Ia):

13. The method according to claim 12, wherein the compound of formula (Ia) is a compound of formula (Ia’):(Ia’).

14. The method according to claim 10, wherein the compound of formula (I) is a compound of formula (Ib):(Ib).

15. The method according to claim 10, wherein the compound of formula (I) is a compound of formula (Ic):

16. The method according to any one of claims 10 to 15, comprising administering to the patient the compound of formula (I) in the form of a pharmaceutically acceptable salt.

17. The method according to any one of claims 10 to 16, comprising administering to the patient a mesylate salt of the compound of formula (I).

18. The method according to claim 10, wherein the compound of formula (I) is administered as a salt having formula (Iaa):wherein X- is a pharmaceutically acceptable anion, e.g., Cl- or CH3SO3-.

19. The compound for use according to any one of claims 1 to 9, or the method according to any one of claims 10 to 18, wherein said compound for use or method is comprised within a treatment regimen for treating diabetes, obesity, dyslipidemia, or metabolic syndrome.

20. The compound for use or method according to any one of the preceding claims, wherein the patient has been diagnosed with diabetes, obesity, dyslipidemia, or metabolic syndrome.

21. The compound for use or method according to any one of the preceding claims, wherein the GLP-1 receptor agonist and the compound of formula (I) or pharmaceutically acceptable salt thereof are for administration to the patient in separate, simultaneous, or sequential combination.

22. The compound for use or method according to any one of the preceding claims, wherein the compound of formula (I) or pharmaceutically acceptable salt thereof is for administration to the patient in an amount of from 0.001 to 25 mg / kg / day.

23. The method according to claim 12, comprising administering to the patient the compound of formula (Ia) or pharmaceutically acceptable salt thereof in a form comprising >90% e.e. of the (2aS,4S,6aS,6bS,8aS,8bS,11aS,12aS,12bR) enantiomer of a compound of formula (Ia).

24. The compound for use or method according to any one of the preceding claims, wherein the patient is obese or overweight.

25. The compound for use or method according to any one of the preceding claims, wherein the GLP-1 receptor agonist is a single GLP-1 receptor agonist, dual GLP-1 / GIP receptor agonist, dual GLP-1 receptor agonist / GIP receptor antagonist, triple GLP- 1 / GIP / glucagon receptor agonist, or dual GLP-1 receptor agonist / amylin receptor agonist.

26. The compound for use or method according to any one of the preceding claims, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, dulaglutide, liraglutide, lixisenatide, semaglutide, tirzepatide, cotadutide, noiiglutide, oxyntomodulin, mazdutide, retatrutide, HM15211, UBT251, albiglutide, beinaglutide, PEG- loxenatide, pemvidutide, danuglipron, efpeglenatide, orforglipron, survodutide, maridebart, VK2735, CT-388, CT-996, CT-868, TERN-601, GSBR-1290, CagriSema, and amycretin.

27. The compound for use or method according to any one of the preceding claims, for reducing weakness, reducing fatigue, improving glycemic control, improving endurance exercise capacity, improving skeletal muscle mitochondrial function, improving energy expenditure, improving muscle quality, and / or improving muscle specific force in the patient.

28. A combination comprising, as active components, a GLP-1 receptor agonist and a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein U is carbon; n is 0 or 1; dashed bond (------) represents a single or double bond; • when the dashed bond (------) represents a single bond, n is 1, and R1aand R1b, together with U, form a methylpiperidine ring of formula:• when the dashed bond (------) represents a double bond, n is 0, and R1ais – CH2CH2CH(CH3)CH2NH2; and R2is H or, wherein represents the point of attachment to the oxygen.

29. The combination according to claim 28, for administration in separate, simultaneous, or sequential dosage forms.

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